NOVEL RECEPTOR-TYPE PHOSPHOTYROSINE PHOSPHATASE-KAPPA

Abstract: A novel receptor-type protein tyrosine phosphatase- kappa (RPTP kappa ) protein or glycoprotein and the DNA coding therefor is expressed in a wide variety of mammalian tissues. The RPTP kappa protein or glycoprotein may be produced by recombinant means. Antibodies to the protein, methods for measuring the quantity of the protein, methods for screening compounds, such as drugs, which can bind to the protein and inhibit or stimulate their enzymatic activity, are provided. Further, methods for inhibiting homophilic binding of Type II RPTP, especially RPTP kappa molecules are provided.

Description: NOVEL RECEPTOR-TYPE PHOSPHOTYROSINE PHOSPHATASE- APPA 1 . INTRODUCTION s The invention in the field of biochemistry and cell and molecular biology relates to novel receptor- type protein tyrosine phosphatase protein or glycoprotein, termed RPTP/c (also known as RPTPase-i) , 0 DNA coding therefor, methods for production and identification of the protein, methods for screening compounds capable of binding to and inhibiting or stimulating PTPase enzymatic activity, methods for inhibiting homophilic binding of RPTP/c, and methods 5 for identifying compounds which are capable of inhibiting homophilic RPTP/c binding. 2. BACKGROUND OF THE INVENTION 0 Tyrosine phosphorylation of proteins is involved in an increasing number of cellular signalling events. It was originally implicated in signalling by paracrine- or autocrine-acting growth factors, and endocrine hormones such as insulin (see Yarden, Y. et 5 al., Annu. Rev. Biochem. 57:443-478 (1988) for review) . It is now clear that this posttranslational modification is also involved in diverse processes such as the activation of cells of the immune system by antigens (Klausner, R.D. et al . , Cell 64:875-878), 0 signalling by lymphokines (Hatakeyama, M. et al. , 1991 Science 252:1523-1528 (1991); Mills, G.B. et al. , J. Biol. Chem. 265:3561-3567 (1990)), and cellular differentiation and survival (Fu, X.-Y. 1992 Cell 70:323-335; Schlessinger, J. et al. 1992 Neuron 9:1- 5 20; Velazquez, L. et al . , 1992 Cell 70:313-322). In view of the diversity of processes in which tyrosine phosphorylation is involved, it is not surprising that links are also emerging with the process of cell adhesion and cell-cell contact. The identification of several growth factor receptors and retroviral oncogenes as tyrosine- specific protein kinases indicated that protein phosphorylation on tyrosine residues plays a key role in cellular growth control. This notion has recently received support by the observation that the level of tyrosine phosphorylation of enzymes thought to play an important role in signal transduction (such as phospholipase C) correlates with their increased activity upon growth factor stimulation, thus establishing a functional role for tyrosine phosphorylation (Ullrich, A., et al.. Cell 61:203-212 (1990)) . Most of the processes in which tyrosine phosphorylation is implicated involve the transduction of a signal through the cell membrane. In its best understood fashion, this can occur through dimerization-mediated activation of members of the receptor tyrosine kinase family by soluble ligandε (reviewed in Ullrich, A. et al. 1990 Cell 61:203- 212) . However, modulation of receptor tyrosine kinase activity can also occur by membrane-bound ligands on neighboring cells, as in the case of the interaction between the sevenless kinase and the bride of sevenless protein (Rubin, G.M. 1991, Trends in Genetics 7:372-376). Recently, receptor-like tyrosine kinases were described with an extracellular domain similar to that of cell adhesion molecules of the CAM- family (e.g. Axl and Ark (O'Bryan, J.P. et al. , 1991 Mol. Cell. Biol. 11:5016-5031; Rescigno, J. et al. , 1991 Oncogene 6:1909-1913)). Such observations may implicate tyrosine phosphorylation as a more broadly used direct downstream effector mechanism for precise cell-cell recognition and signalling events. Members of the non-receptor family of tyrosine kinases have also in several instances been shown to be associated with other proteins with a trans-membrane topology, examples being the association of the Lck and Fyn kinases with the CD4 protein and T-cell receptor complex components respectively (Haughn, L. et al., 1992 Nature 358:328-331; Samelson, L.E. et al . , 1992 Proc . Natl . Acad . Sci . USA 87:4358-4362; Veillette, A. et al., 1988 Cell 55:301-308). However, the mechanism by which kinase activity is modulated in these instances is not understood. The degree and pattern of phosphorylation of tyrosine residues on cellular proteins are regulated by the opposing activities of protein-tyrosine kinases (PTKases; ATP:protein-tyrosine O-phosphotransferase, EC 2.7.1.112) and protein-tyrosine-phosphatases (PTPases; protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48). The structural characteristics and evolution of PTKases as well as their role in the regulation of cell growth have been reviewed (Hunter, T. , et a . , Annu . Rev. Biochem . 54:897-930 (1985); Ullrich, A., et al . , supra) . 2.1. PTKases Tyrosine kinases comprise a discrete family of enzymes having common ancestry with, but major differences from, serine/threonine-specific protein kinases (Hanks, S.K. et al . , (1988) Science 241:42- 52) . The mechanisms leading to changes in activity of tyrosine kinases are best understood for receptor-type tyrosine kinases which have a transmembrane topology (Ullrich, A. et al . , supra) . With such kinases, the binding of specific ligands to the extracellular domain of these enzymes is thought to induce their oligomerization leading to an increase in tyrosine kinase activity and activation of the signal transduction pathways (Ullrich, A. et al . , supra) . The importance of this activity is supported by the knowledge that dysregulation of kinase activity through mutation or over-expression is a mechanism for oncogenic transformation (Hunter, T. et al., supra ; Ullrich, A. et al . , 1990, supra) . 2.2. PTPases The protein phosphatases are composed of at least two separate and distinct families (Hunter, T. Cell, 58:1013-1016 (1989)), the protein serine/threonine phosphatases and the protein tyrosine phosphatases. This is in contrast to protein kinases, which show clear sequence similarity between serine/threonine- specific and tyrosine-specific enzymes. There appear to be two basic types of PTPase molecules. The first group is comprised of small, soluble enzymes that contain a single conserved phosphatase catalytic domain, and include (1) placental PTPase IB (Charbonneau, H. et a ., Proc . Natl . Acad . Sci . 86:5252-5256 (1989); Chernoff, J. et al . , Proc . Natl . Acad . Sci . USA 87:2735-2789 (1990)), (2) T-cell PTPase (Cool, D.E. et al. , Proc . Natl . Acad. Sci . USA 86:5257- 5261 (1989)), and (3) rat brain PTPase (Guan, K. , et al . , Proc. Natl . Acad . Sci . USA, 87:1501- 1505 (1990). The identification of a tyrosine phosphatase homology domain has raised new interest in the potential of PTPases to act as modulators of tyrosine phosphorylation (Kaplan, R. et al . 1990 Proc. Natl . Acad . Sci . USA 87:7000-7004; Krueger, N.X. et al . , 1990 EMBO J. 9:3241-3252; see, for review, Fischer, E.H. et al . , 1991 Science 253:401-406). The second group of PTPases is made up of the more complex, receptor-linked PTPases, termed R- PTPases or RPTPs, which are of high molecular weight and contain two tandemly repeated conserved domains separated by 56-57 amino acids. RPTPs may be further subdivided into four types based on structural motifs within their extracellular segments. One example of RPTPs are the leukocyte common antigens (LCA) (Ralph, S.J., EMBO J . , 6:1251-1257 (1987); Charbonneau, H. , et al . , Proc . Natl . Acad . Sci . USA, 85:7182-7186 (1988)). LCA, also known as CD45, T200 and Ly-5 (reviewed in Thomas, M.L. , Ann. Rev. Immunol . 7:339-369 (1989)) comprises a group of membrane glycoproteins expressed exclusively in hemopoietic (except late erythroid) cells, derived from a common gene by alternative splicing events involving the amino terminus of the proteins. Other examples of RPTPs are the LCA-related protein, LAR (Streuli, M. et a . , J. Exp . Med . , 168:1523-1530 (1988)), and the LAR-related Drosophila proteins DLAR and DPTP (Streuli, M. , et al. , Proc. Natl . Acad . Sci . USA, 86:8698-8702 (1989)). Jirik et a . screened a cDNA library derived from the human hepatoblastoma cell line, HepG2, with a probe encoding the two PTPase domains of LCA (FASEB J. 4:A2082 (1990) , abstr. 2253) and discovered a cDNA clone encoding a new RPTP, named He-PTP. The HePTP gene appeared to be expressed in a variety of human and murine cell lines and tissues. A large number of members of the RPTP family, called type II RPTPs, display an extracellular domain containing a combination of Ig-domains and fibronectin type III repeats (Fn-III) , features typically encountered in cell adhesion molecules (CAMs) (Gebbink, M.F.B.G. et al . , 1991 FEBS Lett. 290:123- 130; Streuli, M. et al. , 1988 J. Exp. Med. 168: 1523-1530) . An analysis of the expression patten of several R-PTPases in the developing Drosophila CNS suggests some function of these molecules in aspects of axon guidance and outgrowth (Tian, S.S. et al . , 1991 Cell 67:675-685; Yang, X. et a . , 1991. Cell 67:661-673), an observation winch might be related to the ability of R-PTPases to control the activity of src-family tyrosine kinases (Mustelin, T. et al. , 1989 Proc. atl.Acad.Sci.USA 86:6302-6306; Ostergaard, H.L. et al., 1989 Proc. Natl. Acad. Sci. USA 86:8959- 8963; Zheng, X.M. et al., 1992 Nature 359:336-339). Other studies have raised the possibility that certain R-PTPases may function as tumor suppressor genes, e.g. by controlling contact inhibition (LaForgia, S. et al . , 1991 Proc. Natl. Acad. Sci . USA 88:5036-5040). Elevation of cellular phosphotyrosine may occur through mechanisms other than the activation of a tyrosine kinase itself. For instance, expression of the v-crk oncogene, though not a tyrosine kinase, induces the phosphorylation of tyrosine residues through a poorly understood mechanism (Mayer, B.J. et a . (1988) Nature 332 , 272-275) . Potentially, such an outcome could result from either mutation of the substrate or through a general decrease in cellular phosphatase activity, especially in view of the normally high turnover rate of cellular tyrosine- phosphate (Sefton, B.M. et al . (1980) Cell 20:807- 816) . The latter possibility is suggested by the demonstration that tyrosine phosphatase inhibitors can "reversibly transform" cells (Klarlund, J.K. Cell 41 : 707-717 (1985)). PTPases could therefor act as recessive oncogenes. While we are beginning to understand more about the structure and diversity of the PTPases, much remains to be learned about their cellular functions. 5 Thus, a better understanding of, and an ability to control, phosphotyrosine metabolism, requires knowledge not only the role of PTKase activity, but the action of PTPase enzymes as well. It is clear in the art that further delineation of structure-function 0 relationships among these PTPases and RPTP membrane receptors are needed to gain important understanding of the mechanisms of cell growth, differentiation, and oncogenesis. 5 3. SUMMARY OF THE INVENTION The present inventors have conceived of a role for RPTPs in cellular control mechanisms, both as o potential anti-oncogenes, and as effectors in a newly discovered mechanism of transmembrane signalling. They therefore undertook a search for individual RPTP genes and proteins in mammals, including humans, which are potentially involved in such processes, and 5 describe herein the identification of a novel, widely expressed member of the RPTP family, RPTPK, in both mice and in humans which has a transmembrane topology. The novel human RPTP/c disclosed herein consists of two associated subunits whose expression is modulated by 0 cell-to-cell contact, and, in a manner analogous to receptor tyrosine kinases, is subject to direct regulation by extracellular ligands which bind to the extracellular portion. Further, as is demonstrated in the Working Example presented in Section 15, infra . 5 RPTPc is shown to ho ophilically bind other RPTPc molecules. The present invention thus provides a mammalian, preferably a human, receptor-type protein tyrosine phosphatase-κ (RPTPK) protein or glycoprotein molecule, a functional derivative of the RPTPK, or a homolog of the RPTPK in another mammalian species. When the RPTPK molecule is of natural origin, it is substantially free of other proteins or glycoproteins with which it is natively associated. RPTPK is naturally expressed in mammalian brain and is developmentally and anatomically regulated. It is also expressed in other mammalian tissues. The RPTPK molecule of the present invention may also be prepared by chemical synthesis or by or recombinant means. Thus, the substantially pure RPTPK protein or glycoprotein of the present invention may be produced by biochemical purification of the protein or glycoprotein of natural origin or by production using chemical synthesis or by recombinant expression in prokaryotic or eukaryotic hosts. In particular, the invention is directed to a mammalian RPTPK protein or glycoprotein having the amino acid sequence of RPTPK shown in FIG. 3 (SEQ ID NO:l). In another embodiment is provided a functional derivative thereof. Preferably, the RPTPK is of human origin, and has the amino acid sequence SEQ ID NO:2, as shown in FIG. 15(1)-(3). The invention is further directed to a nucleic acid molecule, preferably DNA, which may consist essentially of a nucleotide sequence encoding a mammalian RPTPK having the nucleotide sequence SEQ ID NO:3 (FIG. 1(1) - 1(5)). Preferably, the nucleic acid molecule consists essentially of a nucleotide sequence encoding human RPTPK and having the nucleotide sequence SEQ ID NO:4 or encodes a funcitonal derivative thereof. The DNA molecule is preferably cDNA or genomic DNA. The invention is further directed to the DNA molecule in the form of an expression vehicle, as well as prokaryotic and eukaryotic hosts transformed or transfected with the DNA molecule. Also included in the present invention is a process for preparing a RPTPK protein or glycoprotein, or a functional derivative thereof, comprising: (a) culturing a host capable of expressing the protein, glycoprotein or functional derivative under culturing conditions, (b) expressing the protein, glycoprotein or functional derivative; and (c) recovering the protein, glycoprotein or functional derivative from the culture. This invention is also directed to an antibody, either polyclonal, monoclonal, or chimeric, which is specific for the RPTPK protein or glycoprotein. This invention is also directed to a method for detecting the presence of nucleic acid encoding a normal or mutant RPTPK in a cell or in a subject, com¬ prising: (a) contacting a cell or an extract thereof from the subject with an oligonucleotide probe encoding at least a portion of a normal or mutant RPTPK under hybridizing conditions; and (b) measuring the hybridization of the probe to the nucleic acid of the cell, thereby detecting the presence of the nucleic acid, preferably DNA. The DNA can be selectively amplified, using the polymerase chain reaction, prior to assay. The invention is further directed to a method for detecting the presence, or measuring the quantity of RPTPK in a cell or cells, comprising: (a) contacting said cell or an extract thereof with an antibody specific for an epitope of RPTPK; and (b) detecting the binding of the antibody to the cell or extract thereof, or measuring the quantity of antibody bound, thereby detecting the presence or measuring the quantity of the RPTPK. The present invention is also directed to methods for identifying and isolating a compound capable of binding to RPTPK from a chemical or biological preparation comprising: (a) attaching RPTPK, or the ligand-binding portion thereof, to a solid phase matrix; (b) contacting the chemical or biological preparation with the solid phase matrix allowing the compound to bind, and washing away any unbound material; (c) detecting the presence of the compound bound to the solid phase matrix; and, for purposes of isolation, (d) eluting the bound compound, thereby isolating the compound. Further, the present invention includes a method for identifying an agent capable of stimulating or inhibiting the phosphatase enzymatic activity of RPTPK, comprising: (a) contacting the agent with the RPTPK in pure form, in a membrane preparation, or in a whole live or fixed cell; (b) incubating the mixture in step (a) for a sufficient interval; (c) measuring the enzymatic activity of the RPTPK; (d) comparing the enzymatic activity to that of the RPTPK incubated without the agent, thereby determining whether the agent stimulates or inhibits the enzymatic activity. Still further, the invention provides methods for inhibiting the homophilic binding of Type II RPTP, preferably the homophilic binding of RPTPK, provides methods for identifying agents capable of inhibiting such Type II RPTP homophilic binding, and methods for inhibiting endogenous Type II RPTP homophilic binding in mammalian subjects. 4. DESCRIPTION OF THE FIGURES FIG. 1(1) - 1(5) shows the complete nucleotide sequence and amino acid sequence of murine RPTPK. The signal peptide, A5 homology region, transmembrane domain, and PTPase domains are designated by brackets. FIG. 2 is a schematic representation of the various RPTPK cDNA clones isolated, and the proposed domain structure of the RPTPK protein. Translational start and stop codons as well as restriction sites mentioned in the text are indicated. The vertical arrow indicates the position of the furin cleavage site. TM: transmembrane segment. FIG. 3 shows the predicted amino acid sequence of the RPTPK precursor protein. The putative signal peptide and transmembrane (TM) segment are underlined. The two tandem phosphatase domains are boxed (PTP- l,PTP-2) . The proteolytic cleavage site (RTKR 640- 643) is printed in bold, and the Ig-like domain (Ig, 214-270) shown in bold italic characters. A5: homology to A5 surface protein (Takagi, S. et al . , 1991 Neuron 7:295-307); FN-III: fibronectin type III repeats. The Genbank accession number for the cDNA sequence is L10106. FIG. 4 shows a proposed alignment of the four FN- III repeats of RPTP and domain 7 of human fibronectin (Kornblihtt, A.R. et al . , 1985 EMBO J. 4:1755-1759). Residues most typically conserved in FN-III repeats are highlighted in bold. Residues identical in three or more out of the five aligned sequences are indicated with an asterisk. This region of the protein also contains clearly detectable homology to LAR, Drosophila PTPase 10D, and Drosophila neuroglian, all of which have been reported to contain FN-III repeats. FIG. 5 shows an alignment of the N-terminal domains of RPTPK and mRPTPμ with the cell surface protein A5 (Takagi et al. , supra) . Numbers indicate the first residue of the respective proteins shown in the alignment. Residues marked as consensus are identical between A5 and RPTPK, or between A5 and mRPTPμ. Conservative substitutions are present but not shown. Residues in bold (C,W) define a possible Ig-like domain structure. FIG. 6 shows the expression of RPTPK mRNA in adult tissues using Northern blot analysis of poly(A)+RNA from various mouse tissues. The entire cDNA fragment from clone λ-604 was used as a probe. A similar pattern of hybridization was seen using as a probe the λ-50 cDNA clone and the N-terminal half of the λ-35 cDNA clone. Positions of RNA molecular weight markers, in kb, are indicated on the left side. FIG. 7 is a gel pattern showing the immunoprecipitation of the RPTPK protein. HeLa cells transiently transfected by the calcium phosphate technique with an RPTP-ic expression vector (+) or an empty expression vector (-) were analyzed by radio- immunoprecipitation using antiserum 116 directed against a synthetic peptide corresponding to residues 60 to 76 in the extracellular domain. The immunoprecipitation was performed in the absence (-) or presence (+) of 20 μg of the immunogenic peptide (a-κ: anti RPTPK antiserum 116; pre: corresponding preimmune serum) . Positions of protein molecular weight standards (expressed in kDa) are indicated on the left side of the autoradiogram. FIG. 8 shows the protein tyrosine phosphatase activity of anti-RPTPκ immunoprecipitates. The RPTPK protein was immunoprecipitated from transiently transfected COS cells using anti-N-terminal antibody 116 or corresponding preimmune serum. The PTPase activity in the immune complexes was analyzed in the absence (-) or presence (+) of vanadate. The amount of radioactivity released as inorganic phosphate is expressed as the percentage of the total input radioactivity. A representative of several experiments is shown. FIG. 9 shows RPTPK immunoreactive species in COS cells, and effect of Endo F treatment on SDS-PAGE mobility. Total lysates from mock or RPTPK transfected COS cells were treated or not with Endo F. The lysates were resolved by SDS-PAGE and immunoblotted with anti-N-terminal antibody 116 (left panel) or anti-cytoplasmic antibody 122 (right panel) . The 95 kDa band in panel B also seen in mock- transfected cells is presumably due to fortuitous reactivity of antiserum 122 and not relevant to the analysis. No such protein species was detectable using an antiserum raised against the same antigen in a different rabbit. FIG. 10 shows results of a pulse-chase analysis of RPTPK processing. Mock- transfected cells (lanes 1 and 2) and cells transfected with a wild type RPTPK expression vector (lanes 3 to 6) were etabolically labeled with [ 35 S]- methionine (200 [μCi/ml) for 15 minutes ("pulse") and chased for the time-periods indicated. Immunoprecipitation was performed using antiserum 116. Arrows indicate the positions of the 210 kDa RPTPK precursor and the 110 kDa N-terminal cleavage product. FIG. 11 shows the effect of mutagenesis of the furin cleavage motif RTKR on RPTPK processing. Total lysates from ock-transfected COS cells, cells expressing wt RPTPK, or RPTP(κ) carrying a mutation in the furin cleavage motif RTKR (CM K) were resolved by SDS-PAGE. Immunoblotting was performed using anti-N- terminal antiserum 116 (left panel) , or anti- cytoplasmic antiserum 122 (right panel) . FIG. 12 shows the co-immunoprecipitation of the RPTPK processing products. Total lysate from mock or wild type RPTPK transfected COS cells was subjected to immunoprecipitation using anti-N-terminal antiserum 116, and the precipitate inununoblotted with anti- cytoplasmic antiserum 122. As a control, total lysate from RPTPK transfected cells was loaded in the right lane on the immunoblot. FIG. 13 is a series of micrographs showing the in situ hybridization analysis of RPTPK expression during development and in the adult CNS. Left panel shows localization of RPTPK mRNA in the rat at embryonic day 18. CTX, cerebral cortex; MB, midbrain; SC, spinal cord; L, liver; K, kidney; ϊ, intestine. Right panel shows localization of RPTPK mRNA in a sagittal section of rat brain at postnatal day 6. CTX, cerebral cortex; CB, cerebellum; DG, dentate gyrus. In the cerebral cortex, particularly in the occipital region, the labeling is not uniform in all the cortical cell layers. In the hippocampal formation labeling is more intense in the dentate gyrus and in CA3. In the cerebellum, the most intense labeling is seen in the external granular cell layer. FIG. 14 is a molecular model describing the processing of the R-PTP-K precursor protein. A furin- like endoprotease cleaves the 210 kDa precursor protein, after which both cleavage products (110 and 100 kDa) remain associated. No suggestions as to the mechanism of association are intended. The numerals 116 and 122 designate the sites of epitopes recognized by antisera described in the text. FIG. 15(1)-15(3) shows the nucleotide sequence of the human RPTPK (SEQ ID NO:4) , designated MCP7, and its derived amino acid sequence (SEQ ID NO:2) . FIG. 16. A comparison of the amino acid sequence or RPTPKK to the amino acid sequence of hRPTPμ. Lack of designation of an amino acid in hRPTPμ indicates identity to the MCP7 sequence. The putative signal peptide, the cleavage site and the transmembrane region are underlined, the beginning of each FN-III repeat is indicated. Both PTPase domains are shown with a shaded background. FIG. 17 shows a Northern blot analysis of MCP7 mRNA from human tissues. Poly(A)+RNA (4μg per lane) prepared from the indicated tissues was probed with a 32 p-labeled fragment corresponding to the extracellular domain of MCP7. The blots were applied for a 5 day exposure using an intensifying screen. FIG. 18 shows a Northern blot analysis of MCP7 mRNA from several different human breast cancer cell lines. Poly(A)+RNA ( μg per lane) prepared from the indicated cell line was probed as in FIG. 15 and the blots similarly exposed. FIG. 19 shows gel patterns indicating the transient expression of MCP7 mRNA in transfected cells. Cells of the 293 line were transfected with a MCP7 expression vector (or an empty vector as a control) , metabolically labeled for 24 hours with [ 35 S] methionine and incubated with an anti-N-terminal antiserum 116. Cells were washed, lysed and protein- antibody complexes were removed by protein-A sepharose. Left panel shows a SDS-PAGE gel of immunoprecipitates. Right panel shows Western blots of SDS-PAGE gels of lysates of cells transfected by MCP7-CMV (lane 1) or "empty" CMV (lane 2) and immunoblotted with the anti-N-terminal antiserum 116. FIG. 20 shows Western blot patterns indicating co-expression of MCP7 with different RTKs. Semiconfluent 293 cells were transfected with expression plasmids encoding the indicated RTK together with either an equal amount of MCP7 expression vector or a control plasmid. After stimulation with the appropriate ligand: stem cell factor (SCF) for the pl45 e - it RTK; epidermal growth factor for all other RTKs; insulin for I-R, cells were lysed, aliquots run on SDS-PAGE and transferred to nitrocellulose. Proteins were immunoblotted with anti-phosphotyrosine antibody 5E.2. Molecular mass markers are indicated. FIG. 21 shows Northern blots indicating the relationship between MCP7 mRNA levels and the state of cell confluence in SK-BR-3 cells (left panel) and HT- 29 cells (right panel) in culture. Poly(A)+ RNA (4 μg per lane) was prepared from cells obtained at different levels of confluence (lanes l and 4:40%; lanes 2 and 5: 70%, lane 3 and 6: 100%) and was probed with a 3 P-labeled DNA probe corresponding to the extracellular domain of MCP7 (upper blots) and with a fragment coding for GAPDH (lower blots) . FIG. 22A. Expression of the R-PTPκ protein in transfected S2 cells. Detergent lysates were prepared from transfected cells, resolved by SDS-PAGE, and immunoblotted with an antiserum directed against the extracellular domain of the R-PTPκ protein (Y.-P. Jiang et al . Mol. Cell. Biol. 13, 2942 (1993)). Lanes: 1, R-PTPκ anti-sense transfected cells, not heat-shocked; 2, anti-sense transfected after heat- shock; 3, sense transfected cells, not heat-shocked; 4, sense-transfected cells after heat-shock; 5, lysate from COS cells transiently transfected with an R-PTPκ expression vector (Y.-P. Jiang et al . Mol. Cell. Biol. 13, 2942 (1993)). Molecular weight standards are indicated in kilodaltons. The entire RPTPK cDNA was introduced in both orientations as a Hpal/EcoRV fragment into the Hpal site of a derivative of the pCasper expression vector containing the hsp70 promoter, and the resulting construct co-transfected with the pPC4 plasmid (conferring α-amanitin resistance) into S2 cells using calcium phosphate precipitation. Pools of stably transfected cells were selected in the presence of 5μg/ml α-amanitin for three weeks. Transfected cells were heat-shocked at 37°C for 30 minutes and allowed to recover for 2 hours. Adherent cells were collected, and washed twice in BSS (Kramer, H. et al., 1991, Nature 352:207; Snow, P. et al., 1989, Cell 5-9:313). FIG. 22B. Photographs of transfected cell populations after heat-shock induction and aggregation for 2 hours. Left panel, control (anti-sense transfected) cells; right panel, cells transfected with an expression vector carrying the R-PTPκ cDNA in the sense orientation; insert: higher magnification of a typical aggregate. FIG. 22C. Time-course and quantitation of aggregation by Coulter-counting of above-threshold particles. Open squares: anti-sense vector transfected cells, uninduced; full squares, idem, induced; open circles, cells transfected with an expression vector containing the R-PTPκ cDNA in the sense orientation, uninduced; full circles, sense, induced. Standard errors are indicated by error bars. Adherent, transfected cells were collected, washed twice with BSS, resuspended in BSS at a concentration of 4xl0 6 cells/ml, and incubated in Coulter-Counter vials on a rotary shaker for 2 hours at 100 rpm at room temperature. For each time-point, 1 ml was counted using the Coulter-counter with the following settings: 1/amplification=4; threshold=10; 1/aperture current=32. FIG. 22D. Effect of deletion of the intracellular domain of the R-PTPκ protein, and mutation of the furin cleavage site. Parental S2 cells were transiently transfected with expression vectors encoding an R-PTPκ cDNA in which the furin cleavage site had been mutated (CM) (Y.-P. Jiang et al . Mol. Cell. Biol. 13, 2942 (1993)), a cDNA encoding a catalytically inactive deletion mutant of R-PTPκ lacking most of the intracellular (PTPase) domain (Δ- PTP) , or a wt R-PTPK CDNA (wt) . For the deletion mutant, a cDNA encoding a truncated, catalytically inactive form (ΔK) of RPTPK was constructed by restriction digestion with BspEI and Klenow fill-in of the wild type cDNA. This leads to the introduction of a stop codon after amino acid residue 1083, and the generation of a protein lacking the cysteine residues essential for catalysis in the two intracellular catalytic homology domains of RPTPK. Cells were heat- induced 72 hours after transfection, subjected to aggregating conditions for 2 hours, and above- threshold aggregates counted with a Coulter-counter. Error bars indicate standard errors. Transfected, but non heat-shock induced cells behaved as untransfected parental cells. The apparent differences in aggregation intensity between the different forms of R-PTPK may reflect protein expression levels. The numbers provided by Coulter-counter counting actually provide an underestimation of the amount of aggregation as determined by visual inspection and counting of aggregates, since only large particles above a certain threshold size are scored by the Coulter-Counter. FIG. 23. Aggregates consist solely of cells expressing the R-PTPκ protein. Two different cell populations, one of which had been labeled with the fluorescent dye dil (J. Schlessinger et al . Science 195. 307 (1977) , were allowed to co-aggregate and the resulting aggregates inspected by visible and fluorescence microscopy, dil-fluorescence is white in the photographs. Left: a pool of R-PTPκ expressing cells was allowed to aggregate in the presence of an equal number of dil- stained R-PTPκ-negative cells. Middle: R-PTPκ expressing cells were stained with dil and allowed to aggregate in the presence of unstained RPTPK-negative cells. Right: mixture of stained and unstained R-PTPκ- positive cells. In each case, ten aggregates were randomly localized under visible light only. Subsequent inspection under U.V. light consistently showed the staining pattern exemplified in the photographs, dil dye (Molecular Probes, Inc.) was added to the growth medium at a concentration of 3.2μM during heat shock, and washed away prior to recovery and assay. 2xl0 6 cells of each population were mixed and allowed to co-aggregate in a total volume of 1 ml. FIG. 24. Adhesion of R-PTPκ transfected cells to a surface coated with recombinant purified R-PTPκ extracellular domain protein. R-PTP -negative, 1, or positive, 2, S2 cells, or R-PTPκ-negative, 3, and positive, 4, L6 cells were incubated with a surface partially coated with the K2AP protein (circle) , and the adherent cells fixed and stained. Amino acids 1- 639 of the RPTPK proprotein were fused in-frame with human placental alkaline phosphatase in the vector pBacblue III (Invitrogen) by a series of appropriate cloning steps. Recombinant virus was generated and used to infect High-Five cells for production of the K2AP fusion protein using standard procedures. A secreted alkaline phosphatase (AP) control protein was generated in L6 myoblast cells by stable transfection with a modified version of the AP-TAG vector encoding a fusion protein of AP with a signal peptide. Both proteins were affinity purified by elution from an anti-alkaline phosphatase monoclonal antibody (Medix Biotech) column using 100 mM diethanolamine pH 11.5, or 50% ethylene glycol, dialyzed against PBS, and stored at 4°C. The K2AP and AP proteins were approximately 90% and 50% pure, resp. as determined by silver staining. To generate a mammalian cell line expressing the RPTPK protein, an MJ 30-based RPTPK expression vector was co-transfected with pSVneo into L6 cells, and individual clones surviving G418 selection screened for expression using immunoblotting. This procedure did not detect endogenous RPTPK protein in the parental L6 cells. The expressed protein underwent appropriate furin cleavage as described (Jiang, Y.-P. et al., 1993, Mol. Cell. Biol. H:2942) . For adhesion assays, 4μl aliquots of protein samples (20μg/ml) were spotted on 35 mm bacteriological Petri dishes and incubated at room temperature for 30 minutes. The solutions were removed by aspiration, and the surface of the entire plate blocked with 1% heat-inactivated BSA for 60-90 minutes. The plates were incubated with a suspension of S2 cells (4xl0 6 /ml) in BSS with shaking (50 rpm) for one hour at room temperature, or with L6 cells in S- MEM (2xl0 6 /ml) without shaking, at 37°C, washed three times with PBS, fixed and stained. DETAILED DESCRIPTION OF THE INVENTION Through the use of recombinant DNA methods, the present inventors have identified novel mammalian receptor-type (transmembrane) protein tyrosine phosphatases (PTPase; EC 3.1.3.48). In view of its receptor-like structure, and the likelihood that it is part of a family, the inventors have termed this protein, RPTPK (receptor protein tyrosine phosphatase- JL) . The family is designated herein as the "RPTPs." Human RPTPK has 1444 amino acids (SEQ. ID N0:2) . Human RPTPK (also designated MCP7) has an extracellular domain composed of one "MAM" domain, which is a sequence motif spanning about 170 amino acid residues, which was recently established by comparison of several functionally diverse receptors (including RPTPμ and the A5 protein) and is thought to play a role in cell adhesion (Beckmann & Bork, 1993, TIBS -18:40-41) . The extracellular domain further includes one Ig-like, and four FN-type Ill-like segments. It therefore shares structural features with some cell adhesion molecules, permitting the classification of RPTPK into the type II PTPase class. The cDNA cloning of human RPTPK and the complete DNA and amino acid sequences of human RPTPK and its murine homologue are described herein. Northern analysis has been used to identify the natural expres¬ sion of the protein in various cells and tissues. A partial cDNA clone of the catalytic domain of RPTP /HPTPK has been previously described (commonly assigned U.S. Patent Application Serial No. 07/654,188, from which the present application claims priority; Kaplan et al . , Proc. Natl . Acad. Sci . 87:7000-7004 (1990); Krueger et al . , EMBO J . 9:3241- 3252 (1990)). RPTPK has been shown to be expressed in anatomically distinct regions of rat brain and its expression has been found to be developmentally regulated. Remarkably, in addition to being composed of intracellular domains having enzymatic activity, the receptor family to which RPTPs belong includes transmembrane proteins having and N-terminal extracellular domains, analogous to the tyrosine kinase enzyme family (Tonks, N.K. et a . (1988) Biochemistry 27:8695-8701; Charbonneau, H. et al . (1988) Proc . Natl . Acad . Sci . USA 85:7182-7186; Streuli, M. et al . (1988) J. Exp. Med . 168:1523- 2530; Streuli, M. et al . (1989) Proc. Natl . Acad . Sci . USA 86:8698-8702) . The present inventors have therefore concluded that ligands in the extracellular environment can control the activity of this membrane- associated subclass of PTPases. Further, results presented in the current invention demonstrate that Type II RPTPs undergo homophilic binding, i.e.. Type II RPTP receptor molecules have the ability to bind to each other. Homophilic binding, as defined here, may include intercellular binding and/or binding of at least two Type II RPTP receptor proteins present on the surface of the same cell. In addition, homophilic binding may include not only binding of identical Type II RPTP molecules to each other, for example binding of at least two RPTPK molecules to each other, but may also include the binding of any two Type II RPTP molecules to each other, such as, for example, the binding of RPTPK to another Type II RPTP molecule. As demonstrated in the Working Example presented in Section 15, below, RPTPK undergoes intercellular homophilic binding to other RPTPK molecules. This result represents the first example of such a homophilic binding mechanism observed within the RPTP family of molecules, and provides a link between cell- cell contact and cellular signaling events involving tyrosine phosphorylation. RPTPK is useful in methods for screening drugs and other agents which are capable of activating or inhibiting the PTPase enzymatic activity, and thereby affecting major pathways of cellular metabolism. By attaching an intact RPTPK, or the ligand-binding portion thereof, to a solid phase matrix, an affinity probe is created which can be used to screen biological products or chemical agents for their capacity to interact with the receptor on the basis of their binding activity. Bound material can then be eluted from the affinity probe in purified form. RPTPK is also useful in methods for screening drugs and other agents which are capable in inhibiting Type II RPTP homophilic binding, and thus affecting major processes involving, but not limited to, cell- cell and/or cell-ECM (extracellular matrix) interactions. By attaching an intact Type II RPTP such as RPTPK, or an extracellular domain thereof, to a solid matrix, drugs or other agents may be screened for their ability to bind the RPTP. Those agents which bind the RPTP with specificity may be eluted off the solid phase matrix in purified form and further tested for their ability to inhibit RPTP homophilic binding. Note that it is intended to be within the scope of this invention that the inhibition of RPTP homophilic binding described herein refers to not only the binding of at least two identical Type II RPTP molecules, such as at least two RPTPK molecules to each other, but also to binding of any Type II RPTP class of molecules to each other, such as, for example, the binding of RPTPK to another Type II RPTP molecule. Potential agents which may inhibit such Type II RPTP binding may include, but are not limited to, soluble portions of Type II RPTP extracellular domains, antibodies directed against Type II RPTP extracellular domain epitopes, or small synthetic molecules. RPTP extracellular domains may include all or any inhibitory portion of the MAM, Ig, and/or fibronectin Type III (FN-III) domains, as well as peptides which include the HAV, and/or the RXR/LR consensus sequences, as described below. Any of the inhibitory compounds which inhibit homophilic RPTP binding may but are not required to modulate the phosphatase activity of the RPTP molecules whose binding capability is affected. Further, the ability of a compound to inhibit Type II RPTPK homophilic binding may be tested in a variety of ways. RPTPK will be used as an example, but it should be kept clear that such techniques may be used for any Type II RPTP molecule. RPTPK, or an extracellular domain thereof, may first be immobilized by attachment to a solid matrix, using techniques well known to those of ordinary skill in the art. Such a solid matrix may include but is not limited to a petri dish, microtiter well, or a glass, plastic or agarose bead. Second, RPTPK, either in a purified protein form or, alternatively, present in a cell membrane preparation or present on the surface of an intact cell, may be incubated in the presence of the solid matrix together with a compound of interest. The ability of the compound to inhibit RPTRK homophilic binding to the solid matrix may then be assayed by determining if RPTPK molecules bind the immobilized molecules. Such a determination may be accomplished using a variety of techniques well known to those of ordinary skill in the art and include, but are not limited to the labelling of the RPTPK present in purified form, in a cell membrane preparation, or in an intact cell. Alternatively, a compound of interest may be tested by incubating RPTPκ-expressing cells in the presence of the compound of interest and subsequently assaying the ability of the cells to undergo aggregation. Aggregation assays may include, but are not limited to directly counting aggregates using the aid of a microscope, and/or determining super-threshold particles with a coulter-counter. Methods for coupling proteins and peptides to a solid phase matrix or carrier, the solid phase matrix materials useful in these methods, and means for elution, are well known to those of skill in the art. The RPTPK protein, or derivatives thereof having enzymatic activity, can be used for testing agents or compounds capable of enhancing or inhibiting the phosphatase activity. The ability of a compound under test to modify phosphatase activity can be tested in an in vitro system wherein the test compound is added to purified RPTPK protein, or an enzymatically active derivative thereof, and the effects on enzyme activity measured using standard enzymological procedures well known to those of skill in the art. Alternatively, the action of a compound on RPTPK enzymatic activity can be measured in a whole cell preparation using live or fixed cells, or a membrane fraction derived from live or fixed cells. This method is useful for screening compounds acting via the extracellular receptor portion of the protein, as well as compounds acting directly on the enzymatic portion of the protein. A test compound is incubated with cells, or with a membrane preparation derived therefrom, which express high amounts of RPTPK, such as transfected COS or NIH-3T3 cells. The amount of cellular phosphotyrosine is then measured, using methods well-known in the art (Honegger, A.M. et al . , Cell 51:199-209 (1987); Margolis, B. et al . , Cell 57:1101-1107 (1989)). The results are compared to results obtained in the absence of the test compound, or in the absence or presence of a known activator of RPTPK enzymatic activity. In such studies, the action of the test compound in the presence of an activator of tyrosine kinase can also be measured. A compound which stimulates RPTPK enzymatic activity will result in a net decrease in the amount of phosphotyrosine, whereas a compound which inhibits RPTPK enzymatic activity will result in a net increase in the amount of phosphotyrosine. Compounds which inhibit homophilic Type II RPTP binding may also modulate the enzymatic activity of the RPTP molecules they affect, either by increasing or decreasing the RPTPs' phosphatase activity. In the case of growth factor receptors which are tyrosine kinases, such as the receptors for epidermal growth factor (EGF) and for platelet-derived growth factor (PDGF) , tyrosine phosphorylation is linked to cell growth and to oncogenic transformation. Activation of a PTPase, leading to dephosphorylation, would serve as a counterregulatory mechanism to prevent or inhibit growth, and might serve as an endogenous regulatory mechanism against cancer. Thus, mutation or dysregulation of this receptor/enzyme system may promote susceptibility to cancer. Inhibitory compounds which are found that are capable of inhibiting Type II RPTP homophilic binding may be used to modulate a variety of cellular processes including, but not limited to those involving cell-cell and/or cell-ECM interactions. Such processes include, but are not limited to normal cellular functions such as differentiation and cell cycle control; normal cellular behaviors including, but not limited to motility, contact inhibition, cell adhesion, and signal transduction; and abnormal or potentially deleterious processes such as cellular transformation to a cancerous state. Inhibitory compounds which inhibit Type II RPTP homophilic binding may be used to modulate such processes in mammals by administration of an effective concentration of the inhibitory compound to a mammal, using techniques well known to those of ordinary skill in the art. Inhibitory compounds may include, but are not limited to, compounds comprising soluble RPTP Type II extracellular domains, for example, soluble RPTPK extracellular domains. Depending on the conditions being treated, agents may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. Suitable routes may include oral, rectal, trans ucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventicular, intravenous, 5 intraperitoneal, intranasal, or intraocular injections, just to name a few. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution. Ringer's solution, or 0 physiological saline bffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. The insulin receptor is also a tyrosine kinase, and phosphorylation of tyrosine in cells bearing insulin receptors would be associated with normal physiological function. In contrast to the case of cell growth and cancer, activation of an RPTP would counteract insulin effects. Subnormal RPTP levels or o enzymatic activity would act to remove a normal counterregulatory mechanisms. Perhaps more important, though, over-activity, or inappropriate activation, of an RPTP, such as RPTPK, would be expected to partially or totally inhibit the action of insulin on cells, 5 leading to diabetes (of an insulin-resistant variety) . Thus, susceptibility to diabetes may be associated with RPTPK dysregulation. Therefore, the methods of the present invention for identifying normal or mutant genes encoding RPTPK, 0 or for measuring the amount or activity of RPTPK associated with a cell or tissue, can serve as methods for identifying susceptibility to cancer, diabetes, or other diseases associated with alterations in cellular phosphotyrosine metabolism. 5 The present invention provides methods for evaluating the presence of, and the level of, normal or mutant RPTPK in a cell or in a subject. Absence, or more typically, low expression of the RPTPK, or presence of a mutant RPTPK, in an individual may serve as an important predictor of susceptibility to oncogenic transformation and the development of cancer. Alternatively, over-expression of RPTPK, possibly due to a mutant receptor/enzyme system insensitive to negative regulation, or due to overabundance of a stimulatory ligand in the body, may serve as an important predictor of susceptibility to diabetes. An oligonucleotide probe corresponding to a DNA sequences encoding a part of RPTPK (see below) is used to test cells from a subject for the presence of DNA or RNA sequences encoding the RPTPK A preferred probe would be one directed to the nucleic acid sequence encoding at least 4 amino acid residues, and preferably at least 5 amino acid residues, of the RPTPK. Qualitative or quantitative assays can be performed using such probes. For example. Northern analysis (see Section 7, below) is used to measure expression of an RPTPK mRNA in a cell or tissue preparation. Such methods can be used even with very small amounts of DNA obtained from an individual, following use of selective amplification techniques. Recombinant DNA methodologies capable of amplifying purified nucleic acid fragments have long been recognized. Typically, such methodologies involve the introduction of the nucleic acid fragment into a DNA or RNA vector, the clonal amplification of the vector, and the recovery of the amplified nucleic acid fragment. Examples of such methodologies are provided by Cohen et al. (U.S. Patent 4,237,224), Sambrook et al . , MOLECULAR CLONING : A LABORATORY MANUAL , Second Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (1989) , which references are herein incorporated by reference) . An in vitro enzymatic method which is capable of increasing the concentration of such desired nucleic acid molecules is called the "polymerase chain reaction or "PCR" (Mulliε, K. et al . , Cold Spring Harbor Symp. Quant . Biol . 51:263-273 (1986); Erlich, H. et al., EP 50424, EP 84796, EP 258017, EP 237362; Mulliε, K., EP 201184; Mulliε, K. et a . , US 4,683,202; Erlich, H., US 4,582,788; and Saiki, R. et al . , US 4,683,194) . The PCR provides a method for selectively increasing the concentration of a particular nucleic acid sequence even when that sequence has not been previously purified and is present only in a single copy in a particular sample. The method can be used to amplify either single- or double-stranded DNA. The method uses two oligonucleotide probes to serve as primers for the template-dependent, polymerase mediated replication of a desired nucleic acid molecule. The precise nature of the two oligonucleotide probes of the PCR method is critical to the success of the method. Polymerase dependent amplification of a nucleic acid molecule proceeds by the addition of a 5' nucleotide triphosphate to the 3' hydroxyl end of a nucleic acid molecule. Thus, the action of a polymerase extends the 3 ' end of a nucleic acid molecule. These inherent properties are exploited in the selection of the oligonucleotide probes of the PCR. The oligonucleotide sequenceε of the probes are εelected εuch that they contain sequences identical to, or complementary to, sequences which flank the particular nucleic acid sequence whose amplification is desired. More specifically, the oligonucleotide sequence of the "first" probe is selected such that it is capable of hybridizing to an oligonucleotide sequence located 3' to the desired sequence, whereas the oligonucleotide sequence of the "second" probe is selected such that it contains an oligonucleotide sequence identical to one present 5' to the desired region. Both probes possess 3' hydroxy groups, and therefore can serve as primers for nucleic acid synthesis. PCR reaction conditions are cycled between (a) those conducive to hybridization and nucleic acid polymerization, and (b) those which result in the denaturation of duplex molecules. In the first step of the reaction, the nucleic acids of the sample are transiently heated, and then cooled, in order to denature any double-stranded molecules. The "first" and "second" probes are then added to the sample at a concentration which greatly exceeds that of the desired nucleic acid molecule. Upon incubation under conditions conducive to hybridization and polymerization, the "first" probe will hybridize to the sample nucleic acid molecule at a position 3' to the sequence to be amplified. If the nucleic acid molecule of the sample was initially double-stranded, the "second" probe will hybridize to the complementary strand of the nucleic acid molecule at a position 3' to the sequence which is the complement of the sequence whose amplification is desired. Upon addition of a polymerase, the 3' ends of the "first" and (if the nucleic acid molecule was double-stranded) "second" probes will be extended. The extension of the "first" probe will result in the εynthesis of an oligonucleotide having the exact sequence of the desired nucleic acid. Extension of the "second" probe will result in the synthesis of an oligonucleotide having the exact sequence of the complement of the desired nucleic acid. The PCR reaction is capable of exponential amplification of specific nucleic acid sequences because the extension product of the "first" probe, of necessity, contains a sequence which is complementary to a sequence of the "second" probe, and thus can serve as a template for the production of an extension product of the "second" probe. Similarly, the extension product of the "second" probe, of necessity, contains a sequence which is complementary to a sequence of the "first" probe, and thus can serve as a template for the production of an extension product of the "first" probe. Thus, by permitting cycles of polymerization, and denaturation, a geometric increase in the concentration of the desired nucleic acid molecule can be achieved. For reviews of the PCR, see: Mullis, K.B. , Cold Spring Harbor Symp. Quant . Biol . 51:263-273 (1986); Saiki, R.K. et al . BioTechnology 3:1008-1012 (1985); Mullis, K.B. et al . Meth . Enzymol . 155:335-350 (1987). In one embodiment, the present invention is directed to a naturally occurring mammalian RPTPK. In another embodiment, the present invention is directed to a recombinant mammalian RPTPK. The preferred mammalian RPTPK of the present invention is of human origin. The invention provides the naturally occurring molecule substantially free of other proteins with which it is natively associated. "Substantially free of other proteins or glycoproteinε" indicates that the protein has been purified away from at least 90 per cent (on a weight baεiε) , and from even at least 99 per cent if desired, of other proteins and glycoproteins with which it is natively associated, and is therefore substantially free of them. That can be achieved by subjecting the cells, tissue or fluid containing the RPTPK to standard protein purification techniques such as an immunoabsorbent column bearing an antibody specific for the protein. Other forms of affinity purification utilize solid-phase substrates which bind the RPTP'ε enzymatic domain, or a ligand that will bind to the receptor domain. Alternatively, the purification can be achieved by a combination of standard methods, such as ammonium sulfate precipitation, molecular sieve chromatography, and ion exchange chromatography. It will be understood that the RPTPK of the present invention can be biochemically purified from a variety of cell or tissue sources. For preparation of naturally occurring RPTPK, tissues such as mammalian brain, especially of human origin, are preferred. Alternatively, because the gene for the RPTPK can be isolated or synthesized, the polypeptide can be synthesized substantially free of other mammalian proteins or glycoproteins in a prokaryotic organism or in a non-mammalian eukaryotic organism, if desired. As intended by the present invention, a recombinant RPTPK molecule produced in mammalian cells, such as transfected COS, NIH-3T3, or CHO cells, for example, is a protein with the naturally occurring amino acid sequence or is a functional derivative thereof. Where a naturally occurring protein or glycoprotein is produced by recombinant means, it is provided substantially free of the other proteins and glycoproteins with which it is natively associated. Alternatively, methods are well known for the synthesis of polypeptides of desired sequence on solid phaεe supports and their subsequent " separation from the support. The present invention provides any of a number of "functional derivatives" of the RPTPK. By "functional derivative" is meant a "fragment," "variant," 5 "analog," or "chemical derivative" of the RPTPK, which terms are defined below. A functional derivative retains at least a portion of the function of the RPTPK, such as (a) binding to a specific antibody, (b) phosphatase enzymatic activity, or (c) binding of the 0 extracellular "receptor" domain to a ligand, which permits its utility in accordance with the present invention. A "fragment" of the RPTPK refers to any subset of the molecule, that is, a shorter peptide. 5 A "variant" of the RPTPK refers to a molecule substantially similar to either the entire peptide or a fragment thereof. Variant peptides may be conveniently prepared by direct chemical synthesis of the variant peptide, using methods well-known in the o ar -• Alternatively, amino acid sequence variants of the peptide can be prepared by mutations in the DNA which encodes the synthesized peptide. Such variants include, for example, deletions from, or insertions or 5 substitutions of, residues within the amino acid sequence. Any combination of deletion, insertion, and substitution may also be made to arrive at the final construct, provided that the final construct possesses the desired activity. Obviously, the mutations that 0 will be made in the DNA encoding the variant peptide must not alter the reading frame and preferably will not create complementary regions that could produce secondary mRNA structure (see European Patent Publication EP 75444) . 5 At the genetic level, these variants ordinarily are prepared by site-directed mutagenesis (as exemplified by Adelman et al . , DNA 2:183 (1983)) of nucleotideε in the DNA encoding the protein or peptide molecule, thereby producing DNA encoding the variant, 5 and thereafter expressing the DNA in recombinant cell culture. The variants typically exhibit the same qualitative biological activity as the nonvariant protein or peptide. An "analog" of the RPTPK refers to a non-natural 0 molecule substantially similar to either the entire molecule or a fragment thereof. A "chemical derivative" of the RPTPK contains additional chemical moieties not normally a part of the peptide. Covalent modifications of the RPTPK 5 protein or of a peptide derived therefrom, are included within the scope of this invention. Such modifications may be introduced into the molecule by reacting targeted amino acid residues of the peptide with an organic derivatizing agent that is capable of o reacting with selected side chains or terminal residues. Cysteinyl residues most commonly are reacted with alpha-haloacetates (and corresponding amines) , such as chloroacetic acid or chloroacetamide, to give 5 carboxymethyl or carboxyamidomethy1 derivatives. Cysteinyl residues also are derivatized by reaction with bromotrifluoroacetone, α-bromo-/3-(5- imidozoyl)propionic acid, chloroacetyl phosphate, N- alkylmaleimideε, 3-nitro-2-pyridyl disulfide, methyl 0 2-pyridyl disulfide, p-chloromercuribenzoate, 2- chloromercuri-4- nitrophenol, or chloro-7-nitrobenzo- 2-oxa-l,3-diazole. Histidyl residues are derivatized by reaction with diethylprocarbonate, pH 5.5-7.0, because this 5 agent is relatively specific for the histidyl side chain. Para-bromophenacyl bromide alεo is useful; the reaction is preferably performed in 0.l M εodium cacodylate at pH 6.0. Lysinyl and amino terminal residues are reacted with εuccinic or other carboxylic acid anhydrides. Derivatization with these agents has the effect of reversing the charge of the lysinyl residues. Other suitable reagents for derivatizing α-amino-containing residues include imidoesters such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; 0- methylisourea; 2,4 pentanedione; and transaminaεe- catalyzed reaction with glyoxylate. Arginyl residues are modified by reaction with one or several conventional reagents, among them phenylglyoxal, 2,3- butanedione, 1,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residues requires that the reaction be performed in alkaline conditions because of the high pK. of the guanidine functional group. Furthermore, these reagents may react with the groups of lysine as well as the arginine e-amino group. The specific modification of tyrosyl residues per se has been studied extensively, with particular interest in introducing spectral labels into tyrosyl residues by reaction with aromatic diazonium compounds or tetranitromethane. Most commonly, N-acetylimidizol and tetranitromethane are used to form O-acetyl tyrosyl specieε and 3-nitro derivatives, respectively. Carboxyl side groups (aspartyl or glutamyl) are selectively modified by reaction with carbodiimides (R'-N-C-N-R') εuch aε l-cyclohexyl-3-(2-morpholinyl- (4-ethyl) carbodiimide or l-ethyl-3-(4-azonia-4,4- dimethylpentyl) carbodiimide. Furthermore, aεpartyl and glutamyl residues are converted to asparaginyl and glutaminyl reεidueε by reaction with ammonium ions. Glutaminyl and asparaginyl residues may be deamidated to the corresponding glutamyl and aspartyl residues, under mildly acidic conditions. Either form of these residues falls within the scope of thiε invention. Derivatization with bifunctional agentε is useful for cross-linking the protein or peptide to a water- insoluble support matrix or to other macromolecular carriers. Commonly used cross-linking agents include, e .g. , l,l-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esterε such as 3,3'- dithiobis(εuccinimidyl- propionate) , and bifunctional maleimideε εuch aε bis- N-maleimido-l,8-octane. Derivatizing agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate yield photoactivatable intermediates that are capable of forming crosslinks in the presence of light. Alternatively, reactive water-insoluble matrices such as cyanogen bromide-activated carbohydrates and the reactive substrates described in U.S. Patent Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537; and 4,330,440 are employed for protein immobilization. Other modifications include hydroxylation of proline and lyεine, phoεphorylation of hydroxyl groupε of seryl or threonyl residues, methylation of the X- amino groups of lysine, arginine, and histidine side chains (T.E. Creightoh, PROTEINS: STRUCTURE AND MOLECULE PROPERTIES , W.H. Freeman & Co. , San Francisco, pp. 79-86 (1983)), acetylation of the N- terminal amine, and, in some instances, amidation of the C-terminal carboxyl groups. Such derivatized moieties may improve the solubility, absorption, biological half life, and the like. The moieties may alternatively eliminate or attenuate any undesirable side effect of the protein and the like. Moieties capable of mediating such effects are disclosed, for example, in REMINGTON' S PHARMACEUTICAL SCIENCES , 16th ed. , Mack Publishing Co., Easton, PA (1980) This invention iε alεo directed to an antibody specific for an epitope of RPTPK, preferably, of human RPTPK, and the use of such an antibody to detect the presence of, or measure the quantity or concentration of, the RPTPK in a cell, a cell or tissue extract, or a biological fluid. The term "antibody" is meant to include polyclonal antibodies, monoclonal antibodies (mAbs) , chimeric antibodies, and anti-idiotypic (anti-Id) antibodies. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of animals immunized with an antigen, preferably the RPTPK protein or glycoprotein, a peptide derived therefrom or an epitope thereof. Monoclonal antibodies are a substantially homogeneous population of antibodieε to εpecific antigens. MAbs may be obtained by methods known to those skilled in the art. See, for example Kohler and Milstein, Nature 256:495-497 (1975) and U.S. Patent No. 4,376,110. Such antibodies may be of any immunoglobulin clasε including IgG, IgM, IgE, IgA, and any εubclaεs thereof. The hybridoma producing the mAbs of this invention may be cultivated in vitro or in vivo . Production of high titers of mAbε in vivo production makeε thiε the preεently preferred method of production. Briefly, cells from the individual hybridomas are injected intraperitoneally into pristane-primed BALB/c mice to produce ascites fluid containing high concentrations of the desired mAbs. MAbs of isotype IgM or IgG may be purified from such asciteε fluids, or from culture supernatants, uεing column chromatography methodε well known to thoεe of skill in the art. Chimeric antibodies are molecules different portions of which are derived from different animal species, such as those having variable region derived from a murine mAb and a human immunoglobulin constant region. Chimeric antibodies and methods for their production are well-known in the art (Cabilly et al, Proc . Natl . Acad . Sci . USA 81:3273-3277 (1984) ; Morrison et a . , Proc. Natl . Acad . Sci . USA 81:6851- 6855 (1984); Boulianne et al.. Nature 312:643-646 (1984); Neuberger et al . , Nature 314:268-270 (1985); Taniguchi et al., European Patent Publication EP171496 (February 19, 1985); Morrison et al . , European Patent Publication EP 173494 (March 5, 1986); Neuberger et al., PCT Publication WO 86/01533 (March 13, 1986); Kudo et al . , European Patent Publication EP 184187 (June 11, 1986); Sahagan et al . , J. Immunol . 137:1066- 1074 (1986); Robinson et al . , International Patent Publication #PCT/US86/02269 (7 May 1987); Liu et al . , Proc . Natl . Acad. Sci . USA 84:3439-3443 (1987); Sun et al., Proc. Natl . Acad . Sci . USA 84:214-218 (1987); Better et al . , Science 240:1041-1043 (1988)). These references are hereby incorporated by reference. An anti-idiotypic (anti-Id) antibody is an antibody which recognizes unique determinants generally aεsociated with the antigen-binding site of an antibody. An anti-Id antibody can be prepared by immunizing an animal of the same species and genetic type (e.g. mouse εtrain) as the source of the mAb with the mAb to which an anti-Id is being prepared. The immunized animal will recognize and respond to the idiotypic determinantε of the immunizing antibody by producing an antibody to these idiotypic determinantε (the anti-Id antibody) . The anti-Id antibody may alεo be used as an "immunogen'' to induce an immune response in yet another animal, producing a so-called anti- anti-Id antibody. The anti-anti-Id may be epitopically identical to the original mAb which induced the anti-Id. Thus, by using antibodies to the idiotypic determinants of a mAb, it is possible to identify other hybrid clones expresεing antibodies of identical specificity. Accordingly, mAbs generated against RPTPK may be used to induce anti-Id antibodies in suitable animals, εuch aε BALB/c mice. Spleen cells from such immunized mice are used to produce anti-Id hybridomas εecreting anti-Id mAbε. Further, the anti-Id mAbε can be coupled to a carrier εuch aε keyhole limpet hemocyanin (KLH) and used to immunize additional BALB/c mice. Sera from these mice will contain anti-anti-Id antibodies that have the binding properties of the original mAb specific for an RPTPK epitope. The anti- Id mAbs thus have their own idiotypic epitopes, or "idiotopes" structurally similar to the epitope being evaluated, such as an epitope of RPTPK. The term "antibody" is also meant to include both intact molecules as well as fragments thereof, such as, for example. Fab and F(ab') 2 , which are capable of binding antigen. Fab and F(ab') 2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have lesε non-specific tisεue binding than an intact antibody (Wahl et al . , J . Nucl . Med . 24:316-325 (1983)). It will be appreciated that Fab and F(ab') 2 and other fragments of the antibodies useful in the present invention may be used for the detection and quantitation of RPTPK according to the methods diεclosed herein for intact antibody molecules. . Such fragments are typically produced by proteolytic cleavage, using enzymes such as papain (to produce Fab fragmentε) or pepεin (to produce F(ab') 2 fragmentε). An antibody is said to be "capable of binding" a molecule if it is capable of specifically reacting with the molecule to thereby bind the molecule to the antibody. The term "epitope" is meant to refer to that portion of any molecule capable of being bound by an antibody which can also be recognized by that anti¬ body. Epitopes or "antigenic determinants" usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three dimenεional structural characteristics as well as specific charge characteristics. An "antigen" is a molecule or a portion of a molecule capable of being bound by an antibody which is additionally capable of inducing an animal to produce antibody capable of binding to an epitope of that antigen. An antigen may have one, or more than one epitope. An antibody is said to be specific for an antigen because it reacts in a highly selective manner, with that antigen and not with the multitude of other antigens which are structurally distinct. The antibodies or antibody fragments of the present invention may be uεed to quantitatively or qualitatively detect the preεence of cellε which express the RPTPK protein. This can be accomplished by immunofluorescence techniques employing a fluorescently labeled antibody (see below) coupled with light microscopic, flow cytometric, or fluorimetric detection. For such methods, the antibody iε preferably εpecific for an extracellular epitope of RPTPK. The antibodieε (or fragments thereof) useful in the present invention may be employed histologically, as in immunofluorescence or immunoelectron microεcopy, for in situ detection of RPTPK. In situ detection may be accomplished by removing a histological εpecimen from a subject, and providing a labeled antibody or antibody fragment of the present invention to such a specimen, preferably by applying or overlaying the antibody over the specimen. Through the use of such a procedure, it is possible to determine not only the presence of RPTPK but also its diεtribution in the examined tissue. Using the preεent invention, thoεe of ordinary skill will readily perceive that any of a wide variety of histological methods (such as staining procedures) can be modified in order to achieve such in situ detection. Such asεayε for RPTPK typically comprise incubating a biological sample, εuch aε a biological fluid, a tiεsue extract, freshly harvested cells, or cells which have been incubated in tissue culture, in the presence of a detectably labeled antibody specific for RPTPK, and detecting the antibody by any of a number of techniques well-known in the art. The biological sample may be incubated with a solid phase support or carrier such as nitrocellulose, or other solid εupport which iε capable of immobilizing cellε, cell particleε or soluble pro¬ teins. The support may then be washed with suitable buffers followed by treatment with the detectably labeled RPTPκ-specific antibody. The εolid phase support may then be washed with the buffer a second time to remove unbound antibody. The amount of bound label on said solid support may then be detected by conventional means. By "solid phase support" is intended any εupport capable of binding antigen or antibodieε. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, and magnetite. The preferred carrier iε totally insoluble in the solution in which the assay of the present invention takes place; partially soluble carriers well-known in the art may also be used. The support material may have virtually any possible structural configuration so long as the support-coupled molecule is capable of binding to an antigen or antibody. Thus, the support configuration may be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface may be flat such as a sheet, test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know many other suitable carriers for binding antibody or antigen, or will be able to ascertain the same by use of routine experimentation. The binding activity of a given lot of anti-RPTPκ antibody may be determined according to well-known methods. Those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation. One of the ways in which the RPTPκ-εpecific anti¬ body can be detectably labeled is by linking the antibody, or a second antibody which binds to the anti-RPTPκ antibody, to an enzyme and use in an enzyme immunoasεay (EIA) . This enzyme, in turn, when later exposed to an appropriate substrate, will react with the εubstrate in such a manner aε to produce a chemical moiety which can be detected, for example, by εpectrophotometric, fluorimetric or by viεual meanε. Enzymes which can be used to detectably label the antibody include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, delta-5- steroid isomerase, yeast alcohol dehydrogenase, alpha- glycerophoεphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphataεe, asparaginase, glucose oxidaεe, beta- galactoεidaεe, ribonuclease, ureaεe, catalase, glucose-6-phosphate dehydrogenase, glucoamylaεe and acetylcholinesteraεe. The detection can be accomplished by colorimetric methods which employ a chromogenic substrate for the enzyme. Detection may also be accomplished by visual comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepared standards. Detection may be accomplished using any of a variety of other immunoassays. For example, by radioactively labeling the antibodies or antibody fragmentε, it iε poεεible to detect RPTPK through the use of a radioimmunoassay (RIA) (see, for example, Work, T.S. et al . , LABORATORY TECHNIQUES AND BIOCHEMISTRY IN MOLECULAR BIOLOGY , North Holland Publishing Company, New York, 1978, which is incorporated by reference herein) . The radioactive isotope can be detected by such meanε as the use of a gamma counter or a εcintillation counter or by autoradiography. It iε also possible to label the antibody with a fluorescent compound. When the fluorescently labeled antibody iε expoεed to light of the proper wave length, itε presence can then be detected due to fluorescence. Among the most commonly uεed fluorescent labelling compounds are fluorescein iεothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o- phthaldehyde and fluorescamine. The antibody can also be detectably labeled using fluorescence emitting metals εuch as l52 Eu, or others of the lanthanide serieε. Theεe metalε can be attached to the antibody uεing εuch metal chelating groups as diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA) . The antibody also can be detectably labeled by coupling it to a chemiluminescent compound. The presence of the chemiluminescent-tagged antibody is then determined by detecting the presence of lumineεcence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester. Likewise, a bioluminescent compound may be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of lumineεcence. Important biolumineεcent compoundε for purpoεes of labeling are luciferin, luciferase and aequorin. The antibody molecules of the present invention may be adapted for utilization in an immunometric asεay, alεo known aε a "two-εite" or "εandwich" assay. In a typical immunometric asεay, a quantity of unlabeled antibody (or fragment of antibody) is bound to a solid support and a quantity of detectably labeled soluble antibody is added to permit detection and/or quantitation of the ternary complex formed between solid-phase antibody, antigen, and labeled antibody. Typical, and preferred, immunometric asεayε include "forward" aεsayε in which the antibody bound to the εolid phase is first contacted with the sample being tested to extract the antigen from the sample by formation of a binary solid phase antibody-antigen complex. After a suitable incubation period, the solid support is washed to remove the residue of the fluid sample, including unreacted antigen, if any, and then contacted with the solution containing a labeled second antibody (which functions as a "reporter molecule") . After a εecond incubation period to permit the labeled antibody to complex with the antigen bound to the solid support through the unlabeled antibody, the solid support is waεhed a εecond time to remove the unreacted labeled antibody. In another type of "sandwich" aεεay, which may also be useful with the antigens of the present invention, the εo-called "εimultaneous" and "reverse" asεayε are uεed. A εimultaneous assay involves a single incubation εtep as the antibody bound to the solid support and labeled antibody are both added to the εample being teεted at the εame time. After the incubation iε completed, the solid support is washed to remove the residue of fluid sample and uncomplexed labeled antibody. The presence of labeled antibody associated with the solid εupport iε then determined as it would be in a conventional "forward" sandwich assay. In the "reverse" assay, stepwise addition first of a εolution of labeled antibody to a fluid εample followed by the addition of unlabeled antibody bound to a εolid εupport after a εuitable incubation period is utilized. After a εecond incubation, the solid phase is washed in conventional fashion to free it of the reεidue of the sample being tested and the εolution of unreacted labeled antibody. The determination of labeled antibody aεsociated with a solid support is then determined aε in the "εimultaneouε" and "forward" assayε. The presence of normally functioning RPTPK in a εubject can alεo be tested using direct enzymatic assays, for the tyrosine phosphataεe activity. Such biochemical measurements can be performed in vitro, using purified enzymes, allowing precise measurements of enzyme activity, or with membrane preparations, or whole cells, where the net phosphotyrosine level is determined. In additional embodiments of the present invention, a nucleic acid molecule, prefereably DNA, comprising a sequence encoding an RPTPK protein and methods for expressing the DNA molecule are provided. One of ordinary skill in the art will know how to identify and clone additional RPTP molecules, of human or other mammalian εpecieε, which have sequence homology to the RPTPK molecules described herein, using the genetic sequences and oligonucleotides of the present invention without undue experimentation. Furthermore, manipulation of the genetic constructs of the present invention allow the grafting of a particular ligand-binding receptor domain onto the transmembrane and catalytic portions of the RPTPK resulting in chimeric molecules. Non-limiting examples of such chimeric molecules include RPTPK wherein the receptor portion is an epidermal growth factor receptor, a fibroblaεt growth factor receptor, and the like. Genetically engineered chimeric recep- torε are known in the art (see, for example, Riedel, H. et al . , Nature 324 : 628-670 (1986)) . Genetic constructs encoding RPTPK, functional derivative thereof, and chimeric molecules such as those described above, can be used in gene therapy. An abnormal or dysfunctional RPTPK, which results in disease, may be replaced by infusion or implantation of cells of the desired lineage (εuch as hemopoietic cellε, neuronε, etc.) transfected with DNA encoding normal RPTPK. Alternatively, or additionally, cellε carrying a chimeric RPTPK having a receptor portion which binds a ligand of choice (e.g., EGF) can be used for such gene therapy. The recombinant DNA molecules of the present invention can be produced through any of a variety of meanε, such aε, for example, DNA or RNA εyntheεis, or more preferably, by application of recombinant DNA techniques. Techniques for synthesizing εuch molecules are diεcloεed by, for example, Wu, R. , et a . (Prog. Nucl . Acid . Res . Molec . Biol . 21:101-141 (1978)), and procedureε for conεtructing recombinant molecules can be found in Sambrook et al . (supra) . Oligonucleotides representing a portion of an RPTPK are useful for screening for the presence of genes encoding εuch proteinε and for the cloning of an RPTPK gene. Techniqueε for synthesizing such oligonucleotideε are diεcloεed by, for example, Wu, R. , et al . , supra . Protein moleculeε are fragmented aε with cyanogen bromide, or with proteaεeε εuch as papain, chymotrypsin, trypsin, etc. (Oike, Y., et a . , J. Biol . Chem . 257:9751-9758 (1982); Liu, C. , et al . , Int . J . Pept . Protein Res . 21:209-215 (1983)). Because the genetic code iε degenerate, more than one codon may be used to encode a particular amino acid (Watson, J.D., In: MOLECULAR BIOLOGY OF THE GENE, 4th Ed., Benjamin/Cummings Publishing Co., Inc., Menlo Park, CA (1987)). Using the genetic code, one or more different oligonucleotideε can be identified, each of which would be capable of encoding the amino acid. The probability that a particular oligonucleotide will, in fact, constitute the actual XXX-encoding sequence can be eεtimated by conεidering abnormal base pairing relationships and the frequency with which a particular codon is actually used (to encode a particular amino acid) in eukaryotic cells. Such "codon usage rules" are disclosed by Lathe, R. , et al., J. Mol . Biol . 183:1-12 (1985). Using such "codon usage rules", a single oligonucleotide, or a set of oligonucleotideε, that contains a theoretical "most probable" nucleotide sequence capable of encoding RPTPK is identified. Although occasionally an amino acid sequence may be encoded by only a single oligonucleotide, frequently the amino acid sequence may be encoded by any of a set of similar oligonucleotideε. Importantly, whereaε all of the members of this set contain oligonucleotides which are capable of encoding the peptide fragment and, thus, potentially contain the same oligonucleotide sequence as the gene which encodes the peptide fragment, only one member of the εet contains the nucleotide sequence that is identical to the nucleotide sequence of the gene. Because this member iε present within the set, and is capable of hybridizing to DNA even in the presence of the other memberε of the εet, it iε poεεible to employ the unfractionated εet of oligonucleotideε in the same manner in which one would employ a single oligonucleotide to clone the gene that encodes RPTPK. The oligonucleotide, or εet of oligonucleotideε, containing the theoretical "most probable" sequence capable of encoding the RPTPK fragment is used to identify the sequence of a complementary oligonucleotide or εet of oligonucleotides which is capable of hybridizing to the "most probable" sequence, or set of sequenceε. An oligonucleotide containing εuch a complementary sequence can be employed as a probe to identify and isolate the RPTPK gene (Sambrook et al. , supra) . A εuitable oligonucleotide, or εet of oligonucleotideε, capable of encoding a fragment of the RPTPK gene (or complementary to εuch an oligonucleotide) iε identified aε above and εynthesized, using procedures well known in the art (Belagaje, R. , et al. , J. Biol . Chem . 254:5765-5780 (1979); Maniatis, T., et al . , In: MOLECULAR MECHANISMS IN THE CONTROL OF GENE EXPRESSION , Nierlich, D.P., et al., Eds., Acad. Preεε, NY (1976); Wu, R. , et al.. Prog . Nucl . Acid Res . Molec . Biol . 21:101-141 (1978); Khorana, R.G., Science 203:614-625 (1979)). DNA εyntheεiε may be achieved uεing an automated synthesizers. The oligonucleotide probe or set is hybridized by meanε well known in the art, againεt a DNA or, more preferably, a cDNA preparation derived from cellε which are capable of expressing the RPTPK gene. Techniques of nucleic acid hybridization are discloεed by Sambrook et al . (supra) , and by Haymeε, B.D. , et al . (In: NUCLEIC ACID HYBRIDIZATION, A PRACTICAL APPROACH, IRL Press, Washington, DC (1985)), which references are herein incorporated by reference. Techniques such aε, or εimilar to, thoεe described above have succeεεfully enabled the cloning of genes for human aldehyde dehydrogenases (Hsu, L.C. et al . , Proc . Natl . Acad . Sci . USA 82:3771-3775 (1985)), fibronectin (Suzuki, S. , et a . , EMBO J . 4:2519-2524 (1985)), the human estrogen receptor gene (Walter, P., et al . , Proc . Natl . Acad . Sci . USA 82:7889-7893 (1985)), tiεsue-type plasminogen activator (Pennica, D. , et al. , Nature 301:214-221 (1983)) and human term placental alkaline phosphatase complementary DNA (Kam, W. , et al . , Proc. Natl . Acad. Sci . USA 82 : (715-8719 (1985)). In a alternative way of cloning the RPTPK gene, a library of expresεion vectorε is prepared by cloning DNA or, more preferably, cDNA (from a cell capable of expreεεing RPTPK) into an expression vector. The library is then screened for members capable of expressing a protein which binds to an anti-RPTPκ antibody, and which has a nucleotide sequence that is capable of encoding a polypeptide that has the same amino acid sequence as all or part of RPTPK. In this embodiment, DNA, or more preferably cDNA, is extracted and purified from a cell which is capable of expreεsing RPTPK protein. The purified cDNA is fragmented (by shearing, endonuclease digestion, etc.) to produce a pool of DNA or cDNA fragments. DNA or cDNA fragments from this pool are then cloned into an expression vector in order to produce a genomic or cDNA library of expression vectors whose memberε each contain a unique cloned DNA or cDNA fragment. An "expression vector" is a vector which (due to the presence of appropriate tranεcriptional and/or translational control sequences) iε capable of expressing a DNA molecule which has been cloned into the vector and of thereby producing a peptide or protein. Expression of the cloned sequenceε occurε when the expression vector is introduced into an appropriate host cell. If a prokaryotic expression vector is employed, then the appropriate host cell would be any prokaryotic cell capable of expressing the cloned εequences. If a eukaryotic expression vector is employed, then the appropriate host cell would be any eukaryotic cell capable of expreεεing the cloned sequenceε. Importantly, εince eukaryotic DNA may contain intervening εequences, and since such sequenceε cannot be correctly proceεsed in prokaryotic cells, it is preferable to employ cDNA from a cell which is capable of expressing RPTPK in order to produce a prokaryotic genomic expression vector library. Procedures for preparing cDNA and for producing a genomic library are disclosed by Sambrook et al . (supra) . A DNA sequence encoding RPTPK of the preεent invention, or encoding functional derivativeε thereof, may be recombined with vector DNA in accordance with conventional techniqueε, including blunt-ended or εtaggered-ended termini for ligation, restriction enzyme digestion to provide appropriate termini, filling in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and ligation with appropriate ligaseε. Techniqueε for such manipulations are disclosed by Sambrook et al. , supra , and are well known in the art. A nucleic acid molecule, such aε DNA, iε "capable of expressing" a polypeptide if it contains nucleotide εequences which contain transcriptional and translational regulatory information and εuch sequences are "operably linked" to a polypeptide coding sequence. An operable linkage is a linkage in which the regulatory DNA sequences and the coding sequence are connected in εuch a way aε to permit gene expreεsion. The precise nature of the regulatory regions needed for gene expression may vary from organism to organiεm, but εhall in general include a promoter region which, in prokaryotes, containε both the promoter (which directs the initiation of RNA transcription) as well as the DNA sequences which, when transcribed into RNA, will signal the initiation of protein εyntheεiε. Such regions will normally include thoεe 5'-non-coding εequenceε involved with initiation of tranεcription and tranεlation, such as the TATA box, capping sequence, CAAT sequence, and the like. If desired, the non-coding region 3' to the coding sequence may be obtained by the above-described methods. This region may be retained for its tranεcriptional termination regulatory εequences, εuch as termination and polyadenylation. Thus, by retaining the 3'-region naturally contiguous to the DNA coding sequence, the transcriptional termination signalε may be provided. Where the tranεcriptional termination signalε are not satisfactorily functional in the host cell used to express the protein, then a 3' region functional in that host cell may be substituted. Tw° DNA sequences (such aε a promoter region εequence and a RPTPK coding εequence) are said to be operably linked if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame-shift mutation, (2) interfere with the ability of the promoter to regulate the tranεcription of the RPTPK coding εequence. A promoter region iε operably linked to a DNA coding εequence if the promoter iε capable of effecting tranεcription of the coding εequence. Thuε, to expreεε the protein, tranεcriptional and translational signals recognized by an appropriate host are necessary. In order to be "operably linked" it is not necessary that two sequenceε be immediately adjacent to one another. A promoter iε a double-stranded DNA (or RNA) molecule which is capable of binding to RNA polymerase and promoting the transcription of an "operably linked" nucleic acid coding sequence. As used herein, a "promoter sequence" is the εequence of the promoter which is found on that strand of the DNA (or RNA) which is transcribed by the RNA polymeraεe. A "promoter sequence complement" has a sequence which is the complement of the "promoter εequence." Hence, upon extension of a primer DNA or RNA adjacent to a εingle-stranded "promoter sequence complement" or, of a "promoter εequence," a double-εtranded molecule is created which will contain a functional promoter, if that extension proceeds towards the "promoter sequence" or the "promoter εequence complement." This functional promoter will direct the transcription of a nucleic acid molecule which is operably linked to that strand of the double-stranded molecule which contains the "promoter sequence" (and not that strand of the molecule which contains the "promoter sequence complement") . Certain RNA polymerases exhibit a high specificity for such promoters. The RNA polymerases of the bacteriophages T7, T3, and SP-6 are especially well characterized, and exhibit high promoter specificity. The promoter sequences which are specific for each of these RNA polymeraseε also direct the polymerase to transcribe from only one strand of a duplex DNA template. Strand selection is determined by the orientation of the promoter sequence, and determineε the direction of transcription since RNA is only polymerized enzymatically by the addition of a nucleotide 5' phosphate to a 3' hydroxyl terminuε. The promoter sequences of the present invention may be either prokaryotic, eukaryotic or viral. Suitable promoters are repressible, or, more preferably, constitutive. Examples of suitable prokaryotic promoterε include promoters capable of recognizing the T4 (Malik, S. et al . , J. Biol . Chem . 263:1174-1181 (1984); Rosenberg, A.H. et al . , Gene 59:191-200 (1987); Shinedling, S. et al. , J. Molec . Biol . 195:471-480 (1987); Hu, M. et al. , Gene 42:21-30 (1986)), T3, Sp6, and T7 (Chamber1in, M. et al. , Nature 228:227-231 (1970); Bailey, J.N. et a . , Proc. Natl . Acad. Sci . USA 80:2814-2818 (1983); Davanloo, P. et al . , Proc . Natl . Acad . Sci . USA 81:2035-2039 (1984)) polymerases; the P R and P L promoters of bacteriophage λ (THE BACTERIOPHAGE LAMBDA, Hershey, A.D., Ed., Cold Spring Harbor Preεs, Cold Spring Harbor, NY (1973); Lambda II, Hendrix, R.W. , Ed., Cold Spring Harbor Preεs, Cold Spring Harbor, NY (1980)); the trp, recA, heat shock, and lacZ promoters of E. coli ; the α-amylase (Ul anen, I., et al . , J. Bacteriol . 162:176-182 (1985)) and the σ-28-specific promoters of B . subtilis (Gilman, M.Z., et a . , Gene 32:11-20 (1984)); the promoters of the bacteriophages of Bacilluε (Gryczan, T.J. , In: THE MOLECULAR BIOLOGY OF THE BACILLI, Academic Preεε, Inc., NY (1982)); Streptomyceε promoters (Ward, J.M., et al . , Mol . Gen . Genet . 203:468-478 (1986)); the int promoter of bacteriophage λ; the ila promoter of the β-lactamase gene of pBR322, and the CAT promoter of the chloramphenicol acetyl tranεferaεe gene of pPR325, etc. Prokaryotic promoters are reviewed by Glick, B.R. , J. Ind . Microbiol . 1:277-282 (1987)); Cenatiempo, Y. (Biochimie 68:505-516 (1986)); Watson, J.D. et al. (supra) ; and Gottesman, S. Ann. Rev. Genet . 18:415-442 (1984)). Preferred eukaryotic promoters include the promoter of the mouse metallothionein I gene (Hamer, D., et al., J. Mol. Appl. Gen . 1:273-288 (1982)); the TK promoter of Herpes virus (McKnight, S., Cell 31:355-365 (1982)); the SV40 early promoter (Benoist, C, et al.. Nature 290:304-310 (1981)); and the yeast gal4 gene promoter (Johnston, S.A. , et a . , Proc . Natl. Acad. Sci . USA 79:6971-6975 (1982); Silver, P.A., et al., Proc. Natl . Acad. Sci . USA 81:5951-5955 (1984)). All of the above listed references are incorporated by reference herein. Strong promoters are preferred. Examples of such preferred promoterε are those which recognize the T3, SP6 and T7 polymeraseε, the P L promoter of bacteriophage λ, the recA promoter and the promoter of the mouse metallothionein I gene. A most preferred promoter for eukaryotic expression of RPTPK is an SV40 promoter such as that driving transcription in the pLSV vector (Livneh, E. , et al . , (1986) J. Biol . Chem . 261:12490- 12497). The sequences of such polymerase recognition sites are discloεed by Watson, J.D. et a . (supra) . Having now generally described the invention, the same will be more readily understood through reference to the following example which is provided by way of illustration, and is not intended to be limiting of the present invention, unless specified. EXAMPLE: ISOLATION AND ANALYSIS OF MURINE RPTP/c CDNA CLONES In an effort to identify new PTPases, a mouse brain cDNA library in λgtll was screened under relaxed εtringency conditions using aε a probe an oligonucleotide corresponding to the intracellular two tandem PTPase homology domains of human CD45 (Sap et al . , supra) . Following initial characterization and classification of the isolated clones, several subsequent rounds of screening mouse brain libraries at high stringency yielded a set of cDNA fragmentε that together encompassed the entire coding sequence for RPTPK. The relationship between the different RPTPK CDNA clones isolated was confirmed by Northern 5 and reverse transcriptase/PCR analyεeε (see Materials and Methods section and FIG. 2 for details) . 6.1. LIBRARY SCREENING 0 The original RPTPK cDNA clone waε isolated by low- stringency screening of a λgtll mouse brain cDNA library with a probe consisting of the intracellular domain of human CD45, which contains two tandem PTPase domains (see: Sap, J. et al., 1990 Proc. Natl. Acad. 5 Sci. USA 87:6112-6116, for details). After initial characterization, one of the isolated clones (λ-50, containing a 935 nucleotide fragment with characteristic homology to members of the PTPase family) , waε used to rescreen the same library, o yielding clones λ-602 and λ-604. Sequence analysiε εhowed that clone λ-602 waε identical to λ-604 at both extremities, but was interrupted by a sequence containing εtop codonε in all three reading frameε. Itε analysis was therefore discontinued, εince it iε 5 likely to represent an incompletely spliced RNA specieε. By contraεt, λ-604 appeared to contain one PTPaεe homology domain and an additional 2042 nt. of upstream coding sequence, including a likely membrane- spanning region. 0 In order to obtain a full length RPTPK CDNA, the entire insert of clone 604 was used to εcreen another (randomly primed) mouεe brain cDNA library (Clontech) , leading to the iεolation of two hybridizing clones, λ- 35 and λ-37. Clone 35 appeared to overlap with the N- terminus of clone 604 and to encompass the translational initiation codon for the RPTPK precursor protein (see resultε εection) . Initial sequence analysis of clone 37 however revealed no overlap with the clone 604 probe, although it contained a clear additional PTPase homology followed by a stop codon in a position characteristic for the second PTPase domain of a RPTPase. Several controls were used to show that clone 37 corresponds to the bona fide C-terminus of RPTPK. In Northern analysis, clones 37 and 604 recognize identical mRNA species in all mouse tissues examined. A reverse transcriptase/PCR analyεiε on mouse liver poly(A)+ RNA using primers correεponding to clones 604 and 37, followed by cloning and sequencing, yielded a fragment of the expected size, exactly joining both clones at the same EcoRI site where each isolated cDNA clone ended. In retrospect, clone 37 was therefore moεt likely picked up in the εcreening with the clone 604 fragment due to the existence of an additional small cDNA fragment in the original λ-37 phage isolate that went undetected due to its small size, or by fortuitous crosεhybridization between the two PTPase homologies of RPTPK. A schematic summary of the different cDNA clones discussed is included in FIG. 2. 6.2. NUCLEOTIDE SEQUENCE DETERMINATION cDNA fragments were isolated from phage clones, subcloned into Bluescript cloning vectors and subjected to sequence analysis by the dideoxynucleotide chain termination method (Sequenase, United Stateε Biochemical) using synthetic oligonucleotide primers. All εequences were determined on both strands. Sequences were assembled and analyzed using the GCG 7 software package (Devereux, J. et al. , 1984 Nuc . Acids Res . 12:387- 395) . The assembled RPTPK CDNA nucleotide εequence was submitted to Genbank under accession number L10106. 6.3. SEQUENCE ALIGNMENTS All DNA and protein data base searches were done with the Genetic Computer Group sequence analysis software package (Devereux et al . , Nucleic Acid Res . 12:387-396 (1989)). The SwissProt and Gene Bank\European Molecular Biology Laboratory data bases were searched with FASTA and TFASTA, respectively (Pearson and Lipman, Proc . Natl . Acad. Sci . 85:2444- 2448 (1988)). Proteins were aligned with the Geneticε Computer Group programs, LINEUP, PILEUP, PRETTY and BESTFIT. 6.4. RESULTS AND DISCUSSION 6.4.1. ISOLATION AND SEQUENCE ANALYSIS OF cDNA CLONES ENCODING MURINE RPTPK The nucleotide sequence of murine RPTPK (SEQ ID NO:3) iε εhown in FIG. 1(1) - 1(5). The complete amino acid sequences of RPTPK (SEQ ID NO:l) is εhown in FIG. 1(1) through 1(5) and in FIG. 3. The aεεembled RPTPK CDNA εequence can be divided into a 5-untranεlated region of 1072 base pairs, a single open reading frame of 4374 base pairs and a 3' untranεlated region of 388 baεe pairε. The deduced amino acid sequence of the RPTPK precursor protein iε εhown in FIG. 3. The tranεlational initiation codon iε identified by a εtandard environment for initiation of tranεlation (Kozak, supra ) and by the exiεtence of an upεtream in-frame stop codon (position -252) , and is followed by a hydrophobic region that may serve as a signal peptide. A second hydrophobic region is found between amino acid residues 753 and 774 and is 5 followed by a series of predominantly basic residues, characteristic of a stop transfer sequence. These features delineate a putative extracellular region of 752 amino acid reεidues (including the signal sequence) , and an intracellular portion of 683 amino 10 acids. The latter contains the tandem repeat of two PTPaεe homologies typical for most RPTPases isolated so far (Fischer, E.H. et al . , 1991 Science 253:401- 406) . An intriguing feature of RPTPK is the extended ! 5 distance between its trans-membrane segment and the start of the first phosphatase homology domain. This region is about 70 reεidueε longer than in all other previouεly described RPTPases, with the exception of mRPTPμ (Gebbink et al., supra) . 20 Interestingly, a variant of RPTPK waε found by the preεent inventors' laboratory to contain a similarly-sized insertion in the same position. It is conceivable that such an insertion generated by alterative splicing might conεtitute a εeparate 2 5 functional unit in RPTPases. The first approximately 170 amino acids of RPTPK show similarity (26% overall identity) to a region in the Xenopus cell surface protein A5 with features of Ig-like domains (FIG. 5) . The A5 protein is thought 30 to function in recognition between input and target neurons in the visual system (Takagi, S. et al . , 1991 Neuron 7:295-307) . This first domain is followed by one Ig-like repeat (approximately residues 210 to 270) and four 35 putative fibronectin type Ill-like (FN-III) repeats (residues 296 to 681) . Database searching revealed clear εimilarity of theεe FN-III domains to similar domains in the tyrosine phosphataseε R-PTPμ and LAR, the Drosophila R-PTPaseε DLAR and DPTP10D, and Drosophila neuroglian (Bieber, A.J. et al. 1989. Cell 59:447-460; Gebbink et al., supra ; Streuli, M. et al . , 1988, supra ; Streuli, M. et al . , 1989, supra ; Tian et al . , supra ; Yang et al . , supra) . Some other featureε of the extracellular domain of RPTPK are noteworthy. First, it contains the sequence HAV (amino acids 340-342; within the first FN-III repeat) implicated in cell-cell contact in members of the cadherin family (Blaschuk, O.W. et al. , 1990 J.Mol.Biol. 211:679-682). Second, the extracellular domain (640-643) contains the εequence RTKR, a consensus cleavage site for the procesεing endoprotease furin (Hosaka, M. et a ., 1991 _7. Biol . Chem . 266:12127-12130). Other potential posttranslational modification sites include 12 potential N-linked glycosylation sites, and SG-motifs which are candidates for chondroitin sulfate attachment (residueε 172, 176, 277, 333, 662) (Kjellen, L. et al . 1991 Annu. Rev. Biochem. 60:443- 470) . Overall, the εequence of RPTPK εhowε a high degree of sequence εimilarity to mRPTPμ (77% overall similarity at the amino acid level) (Gebbink et a . , supra) . The sequence identity between this pair of related R-PTPaseε iε highest in the first PTPase homology domain (80% as compared to 74% identity for the second PTPase domain) . Thiε iε in contrast to the situation that haε been observed for the relationship between the closely related pairε of R-PTPaεeε LAR and HPTPδ, and RPTP/3/HPTPf and RPTP7 (Kaplan, R. et a . 1990 Proc . Natl . Acad . Sci . USA 87:7000-7004; Krueger, N.X. et al . , 1990 EMBO J. 9:3241-3252; Streuli, M. et al., 1988, supra) . The latter pairs of related R- PTPases are more related in their second PTPase homology domains. The sequence of RPTPK is also highly similar to that of PCR fragment PTP 191-33 described by Nishi, M. et al. , 1990 FEBS Lett. 271:178-180. 7. EXAMPLE: EXPRESSION AND TISSUE DISTRIBUTION OF RPTPK 7.1. TISSUE EXPRESSION AND NORTHERN ANALYSIS Poly(A)+RNA was iεolated from adult mouεe tiεεueε by oligo(dT) selection as described previouεly (Vennstrom, B. et al . 1982 Cell 28:135-143). Five μg of poly(A)+ RNA per lane were fractionated on formaldehyde-containing 1% agarose gels, transferred to Nytran membranes, and probed under high stringency conditions with different regions of the RPTPK CDNA. RNA loading and quality waε controlled for by ethidium bromide staining. 7.1.1. EXPRESSION OF THE RPTPK PROTEIN in order to assemble a full-length RPTPK CDNA from the various isolated fragmentε, a convenient fragment which included the N-terminuε waε generated from clone 35 by a PCR reaction using the N terminal primer 5'GAGCCGCGGCTCGAGTTAACCGCCATGGATGTGGCGGCCG3• (SEQ ID NO:5) and the C-terminal primer 5•GCTCACAGCTAGTTCAGCCC3 ' (SEQ ID NO:6). This manipulation also removed all of the 5'untranεlated εequenceε, while retaining an optimized Kozak consensuε εequence for tranεlation initiation (Kozak, M. 1983 Microbiol . Rev . 47:1-45). The amplified 470 nucleotide product was digested with Sac II and PpuM 1, and cloned between the Sac II and PpuM I sites of clone 604, yielding plasmid ply, (the Sac II site being in the polylinker region of the Bluescript cloning vector). The 1.1 kb Eco RI fragment from clone 37 (containing the c-terminal end of the coding sequence) was then cloned into the unique and corresponding Eco RI site of pKo in the appropriate orientation, yielding construct pK, containing the fully assembled coding sequence without the 5' untranslated sequences. The modified cDNA was then released as one fragment using Hpa I (N-terminal) and Xho I (C-terminal) , and cloned between the Sma I and Sal I εiteε of a CMV-enhancer/promoter-driven eukaryotic expression vector. 7.1.2. GENERATION OF ANTISERA SPECIFIC FOR EPITOPES OF RPTPK Antigenicity of peptides included in the the RPTPK protein was predicted using the Jameson-Wolf algorithm included in the GCG 7 Peptideεtructure program (Devereux, J. et al . , 1984 Nucl. Acids Res . 12:387-395). Two peptideε were εyntheεized. The peptideε were coupled to the protein keyhole limpet hemocyanin by glutaraldehyde croεslinking and injected into rabbitε at two week intervals (100 pg per injection) . The first peptide corresponded to a site near the predicted N-terminus of the RPTPK protein (SEQ ID N0:1), specifically, residues 60-76, having the sequence SAQEPHYLPPEMPQGST. Immunization with this peptide yielded antiserum 116. The second peptide corresponded to a region located at the N-terminus of the first PTPase homology in the intracellular region of the RPTPK protein (SEQ ID NO:l), specifically, residues 910 to 929 having the sequence SASWDVAKKDQNRAK. Immunization with this peptide yielded antiserum 122) (FIG. 14). 7.1.3. TRANSFECTION, LABELING AND IMMUNOPRECIPITATION Subconfluent cultures of COS or HeLa cells in 10 cm diameter disheε (as indicated) were transfected by the DEAE-dextran or calcium phosphate technique, respectively. Between 48 and 72 hours after transfection, the cells were metabolically labeled for 2 hours in methionine-free medium containing 50 μCi/ml [ 35 S]-methionine (ICN) . In the pulse-chaεe analysis shown in FIG. 10, cells were labeled with 200 μCi/ml of the isotope. After labeling, cells were washed in PBS and lysed in Triton-X-100 lysiε buffer (50 mM Hepeε pH 7.5, 150 μM NaCl, 1.5 mM MgCl 2 , 1 mM EGTA, 10% glycerol, 1% Triton-X-100, 200 μg/ml PMSF, 10 μg/ml Aprotinin, 10 μg/ml Leupeptin) at β C Cell lyεateε were incubated at 4°C for 2 hourε with Protein A-Sepharoεe previously preincubated with the respective anti-RPTPκ antibody. Where indicated, 20 μg of the antigenic peptide was included in the immunoprecipitation reaction as a control for εpecificity. Immunoprecipitates were washed with high, medium and low salt buffers (Lev, S. et al . , 1991 EMBO J. 10:647-654), with the exception of the experiment depicted in FIG. 12 where washing was with HNTG-buffer (20 mM Hepes pH 7.5, 150 mM NaCl, 10% glycerol, 0.1% Triton-X-l00) . Immunoblotting analyεeε were performed using standard procedureε. 7.1.4. PROTEIN TYROSINE PHOSPHATASE ENZYMATIC ASSAY Phoεphataεe enzymatic assays were performed with RPTPK protein immunoprecipitated with antiserum 116 (specific for the extracelular domain) from transiently transfected COS cellε. The protein A- Sepharoεe/RPTPκ immunoprecipitated complexeε were washed 4 times with HNTG, and once with M7.6 buffer (60 mM Tris, pH 7.6, 5 mM EDTA, 10 mM DTT, 50 mM NaCl, 50 μg/ml BSA) . The enzymatic assay was performed essentially aε described (Streuli, M. et al. , 1989 Proc . Natl . Acad . Sci . USA 86:8698-8702). The immune complexes were resuspended in 50 μl M17.6 buffer (containing 1 mM vanadate where indicated) to which had been added 10 μl [ 32 P]tyrosine phosphorylated myelin basic protein (approximately 12 μM) . The [ 32 P]-tyrosine- phosphorylated myelin basic protein had been produced by in vitro phosphorylation using EGF-receptor immunoprecipitated from A431 cellε. The reactions were incubated for 15 minutes at 37°C with shaking, stopped with 750 μl of an acidic stop mix containing activated charcoal, and the amount of released free [ 32 P]-phosphate was measured. 7.1.5. ENDOGLYCOSIDASE F TREATMENT Cultures of cells transfected with RPTPK cDNA were lysed in 1% SDS at 100°C for 3 minutes. The total cell lyεateε were εonicated 3 timeε at full speed, then diluted with distilled water to decrease the concentration of SDS to 0.1%. The cell lysateε were incubated at 37°C for 18 hours in the presence of 0.2 unitε endoglycosidase F (Boehringer- Mannheim), 0.25 M sodium acetate, pH 5.2, 20 mM EDTA, 10 mM β- mercaptoethanol and 0.6% NP-40. The total enzyme- treated lysate waε directly loaded onto SDS-PAGE gels, which were run, transferred to nitrocellulose and blotted with antiserum 116 or antiserum 122 aε indicated. 7.1.6. SITE-DIRECTED MUTAGENESIS Jn vitro site-directed mutagenesis was performed using a commercially available kit from Clontech, using the manufacturer's inεtructionε. An oligonucleotide having the εequence CTACACCCACATCTAACGAACCGTGAAGCAGGG (SEQ ID NO:7) was used to modify the amino acid sequence RTKR in the cleavage site to the sequence LTNR. Mutagenesiε waε confirmed by direct DNA εequencing. 7.1.7. IN SITU HYBRIDIZATION OF RPTPK cDNA TO RAT TISSUES Sprague-Dawley rats were sacrificed by decapitation, and their brains were removed and sectioned into 20 μm sectionε in a cryostat. Sections were poεtfixed in 4% paraformaldehyde in 0.1 M εodium phoεphate, pH 7.4, for 20 min. A 50 baεe oligonucleotide complementary to residues 1493-1543 of the isolated RPTPK CDNA εequence (SEQ ID NO:3) waε used as a probe. The oligonucleotide was labeled with [ (o.- 35 S]dATP (NEN, DuPont) using terminal deoxynucleotidyl transferase (Boehringer Mannheim) and purified using Sephadex G25 quick spin columns (Boehringer Mannheim) . The specific activity of the labeled probe was from 2 x 10 8 to 5 x 10 8 cpm/μg DNA. Prehybridization and hybridization were carried out in a buffer containing 50% deionized formamide, 4X SCC, IX Denhardt's εolution, 500 μg/ml denatured εalmon εperm DNA, 250 μg/ml yeast tRNA and 10% dextran εulfate. The tissue sections were incubated in a humidified environment for 14-18 h at 42-46°C in hybridization solution containing the labeled probe and 10 mM dithiothreitol. Specificity controls were performed on adjacent sections by adding to the labeled oligonucleotide a 100-fold excess of the unlabeled oligonucleotide. After incubation, sections were washed in 2 changes of 2X SSC at room temperature 0 for 1 h, then in IX SCC at 50°C for 30 min, 0.5X SCC at 50°C for 30 min, and in 0.5X SCC at room temperature for 10 min. Sections were dehydrated and exposed to X-Omat film for 3 weeks. 5 7.2. RESULTS AND DISCUSSION 7.2.1. EXPRESSION OF RPTPK IN ADULT TISSUES Northern blot analysis on adult mouse tissues o (FIG. 6) revealed that RPTPK expresεion is broad. Two major transcripts of 5.3 and 7.0 kb were detectable at different levels in all examined tisεueε except in εpleen and testis. Particularly high levels of the 5.3 kb transcript were seen in liver and kidney 5 tissue. An identical pattern was detected using as a probe both an N-terminal and central part of the cDNA. Although the 5.3 kb size is εimilar to the 5.7 kb described for mRPTP (Gebbink et a . , supra) , RPTPK appears to be much more widely expresεed than mRPTPμ. 0 Expression of the latter is virtually restricted to lung and, at lower levels, brain and heart. 7.2.2. TRANSIENT EXPRESSION AND ENZYMATIC ACTIVITY OF RPTP/. 5 As described above, the RPTPK coding sequence was cloned into an expression vector under the control of the CMV enhancer and promoter after manipulation to remove the untranslated leader sequence. The construct was transiently transfected into HeLa cells 5 which were metabolically labeled with [ 3S S]-methionine, lysed and subjected to a radioimmunoprecipitation asεay. The antibody probe was an antiserum raised against a peptide located in the N-terminus of the protein (residues 60 to 76) . This antiserum 0 precipitated a protein of about 210 kDa from RPTPK transfected cellε, but not from mock transfected cells (transfected with an "empty'' expreεsion vector) (FIG. 7) . This immunoprecipitation waε blocked by incluεion of the antigenic peptide in the immunoprecipitation 5 reaction (lanes 3 and 6) , but not by inclusion of a heterologouε peptide correεponding to the first catalytic homology domain of RPTPK. To confirm that the protein encoded by the RPTPK cDNA had PTPase enzymatic activity, immune complexes o from transfected cells were incubated in an appropriate buffer with [ 32 P]-tyrosine phosphorylated myelin basic protein as a substrate. As shown in FIG. 8, approximately 3-fold higher PTPase activity was detectable in immune complexes from RPTPK transfected 5 cells as compared to control cellε. This PTPase activity could be significantly inhibited by vanadate. 7.2.3. IN SITU HYBRIDIZATION ANALYSIS OF RPTPK EXPRESSION IN THE DEVELOPING AND ADULT CENRAL 0 NERVOUS SYSTEM The level of expression of RPTPK mRNA waε generally higher in the developing than in the adult central nervouε εyεtem (CNS) . At embryonic day 18 5 (E18) and at E20, the RPTP(κ) mRNA levelε were higheεt in the cerebral cortex and hippocampal formation, followed by the cerebellum, brain stem and spinal cord. In the rest of the embryo, the highest levels were found in the liver, kidney and intestine (left panel, FIG. 13). At postnatal day 6 (P6) and P8, expression was maximal in the cortex, olfactory bulb and hippocampal formation, especially in the dentate gyrus and CA3. In the cerebellum, the expression waε highest in the granular cell layer, which in this stage of development still occupies the outermost cell layer of the cerebellum (right panel, FIG. 13) . In the adult rat, expression waε lower, but was clearly visible in the olfactory bulb and throughout the cortex, including the pyriform and cingulate cortex. Expression of the RPTPK mRNA was also obεerved in the hippocampal formation. Interestingly, expression in the cerebellum was barely detectable in the adult. Thiε waε in marked contraεt with the distinct patten and high level of expression observed t p6 ant * p8 - a period of active cerebellar development. The in situ hybridization studies confirmed the expression of the RPTPK in several organs. In addition, they demonεtrated that, in the CNS, RPTPK iε expressed in specific areas in a developmentally regulated manner. The levels of RPTPK expression are higher in the actively developing areas, but expression persists in the adult, mainly in certain areas of the cortex and in the hippocampal formation. These findings are consiεtent with the idea that CNS RPTPaεes are actively involved in development and plasticity. Studies on the expression of RPTPs in Drosophila have led to εimilar εuggeεtionε (Tian et al . , supra ; Yang et al . , supra) . EXAMPLE: CHROMOSOMAL LOCALIZATION OF THE MURINE RPTPK GENE . The method waε essentially as described previously (Sap, J. et al . , 1990 Proc. Natl . Acad . Sci . USA 87:6112-6116; Silver, J. , 1985 J. Hered. 76:436-440; Taylor, B. , 1978, In: H.C. Morse, III (ed.), ORIGINS OF INBRED MICE, Academic Presε, New York, pp. 423-438; Taylor, B.A. , 1989 In: M.F. Lyon et al . , edε , GENETIC VARIANTS AND STRAINS OF THE LABORATORY MOUSE. Oxford Univerεity Press, New York, pp. 773-796) . Southern blotting analysiε of Taq I- digested mouse genomic DNA with the 604 RPTPK probe revealed an array of 12 fragments that appeared invariant between the inbred strains surveyed, as well as a smaller set of variable bands that were used to define two allelic forms of the gene: (1) a was defined by the presence of 1.9, 3.5 and 3.8 kb fragments and was present in inbred mouse strains AKR/J, C3H/HeJ, DBA/J, SM/J; and (2) b was defined by the presence of a 4.1 kb fragment and waε preεent in inbred mouεe εtrainε C57BL/6J, 020/A, C57L/J, S R/J, SJL/J, BALB/cJ, STS/A, NZB/B1NJ) . Analysis of the inheritance pattern of this variant among recombinant inbred strains of mice (Table I) , and comparison of strain diεtribution patternε thuε obtained with those generated previously for other genetic markers, revealed close linkage between RPTP/c and two markers of proximal chromosome 10: D10Mit3 (2 discordancies among 22 strains typed, indicating a distance of 2.6 cM between the loci (0.3 cM to 13.0 cM defined 95% confidence limitε) ; and Ly- 41 (0 diεcordancies among 30 strains typed, indicating a distance between the loci of < 3.5 cM at 95% confidence) . The gene symbol Ptpk is proposed by the inventors, consistent with the symbol Ptpa previously assigned to RPTPα (Sap et al. , supra) . This region of mouse chromosome 10 contains multiple genes with human homologueε mapping to chromoεome 6q. Baεed on synteny, this would predict a localization of the human RPTPK homologue to 6q, in contrast to 18pter-qll for human RPTPμ (Gebbink et a . , supra) . TABLE I DNA FRAGMENT LENGTH VARIANT ASSOCIATED WITH THE MOUSE RPTP/c GENE. A. Alleles and strain distribution patterns Allele .Size kb.. Strains a 1.9 + 3.5 + 3.8 AKR/J, C3H/HeJ, DBA/2J, SM/J AKXL-5,6,7,8,17,21,25,28,29, 37,38 BXD-1,2,5,14,15,18,21,23,25, 28,32 BXH-2,4,7,8,12,14,19 NXSM-D,L,W,X OXA- ,5,7,8,13 4. 1 C57BL/6J, 020/A, C57L/J, SWR/J,SJL/J, BALB/CJ, STS/A, NZB/B1NJ AKXL-9,12,13,14,16,19,24 BXD-6,8 ,9,11,12,13,16,19,20, 22,24,27,29,30,31 BXH-3,6,9, 10, 11 NXSM-C,E,F,I,N,P,Q,T1,T2,U,Z OXA- 1,2,3,6,9,10,11,12,14 B. Linkage of ptpk to other markers typed in Recombinant Inbred strains Marker Chr R/N Odds Distance fcM. D10Mit3 10 2/22 0.00941 2.6 (0.3-13.0) Ly-41 10 O/30 <0.00001 0.0 (<3.5) A) 10 μg quantities of liver or spleen genomic DNA were digested with Taql enzyme and analyzed by Southern blotting with the 604 RPTPK probe as described previously to define two alleles of the ptpk gene and to follow their inheritance in panels of recombinant inbred (RI) strains of mice. B) The resulting strain distributions were compared with those previously determined for other loci in these panels of mice. Two matches were found that were unlikely to be due to chance at a 5% confidence level. For each of these, the number of non- matching RI strains found (R) is shown as a fraction of the total number of RI strains typed (N) for the two markers, together with the odds of observing that number of non-matches or a smaller one by chance (Blank, R.D. et al . , 1988 Genetics 120:1073-1083), the estimated distance between the marker and ptpk, and the 95% confidence limits for that estimate (Silver, supra ; Taylor, 1978, supra ) . EXAMPLE: POSTTRANSLATIONAL PROTEOLYTIC PROCESSING OF RPTPc During experiments designed to achieve stable expression of RPTP/c in 3T3 cells, the present inventors observed the generation of a product of an unexpected, smaller size as well as the generation of aberrantly-sized products upon transient transfection of COS cells. The present inventors noted the presence of a proteolytic cleavage signal in the extracellular domain of RPTP/c, (RTKR, residues 640 to 643, in the fourth FN-III repeat; FIG. 3) and wished to examine its significance in light of these observations. Thus, additional experiments were performed in COS cells transfected by the DEAE-dextran technique. In order to detect cleavage products which may have accumulated, total cell lysates were directly loaded onto SDS-PAGE gels, run in electrophoresis, transferred to nitrocellulose, and immunoblotted with the two different anti-RPTP/ peptide antisera (described above) specific for either the N-terminus or for an epitope near the first PTPase homology domain in the intracellular portion. In lysates from transfected cells, but not from mock transfected cellε, both antisera recognized the same 210 kDa protein described above. The antiserum specific for the N terminus also recognized a smaller 110 kDa protein. The antiserum specific for the cytoplasmic region recognized a smaller 100 kDa protein (FIG. 9) . The three polypeptides (210, 110 and 100 kDa) were further characterized by subjecting the total cell lysates to endoglycosidase F digestion before SDS-PAGE and immunoblotting. Such a treatment would be expected mainly to affect the mobility of a protein containing the glycosylated extracellular domain. Following endoglycosidase F treatment, the mobility of the 210 kDa and 110 kDa proteins was significantly reduced, to 160 kDa and 89 kDa respectively. In contrast, the mobility of the 100 kDa band detected with antiserum 122 specific for an epitope in the intracellular domain) was only slightly affected, suggesting that the 100 kDa peptide includes a minor glycosylation component (FIG. 9) . The above results, as well as pulse-chase analysis shown in FIG. 10, are consistent with the cleavage of a 210 kDa RPTP/c precursor protein into an N-terminal 110 kDa product encompassing most of the extracellular domain, and a 100 kDa moiety containing the intracellular portion and about 100 residues of extracellular sequence (FIG. 14) . A consensus site for cleavage by furin, a processing endopeptidase (Hosaka et al., supra) , is indeed located 113 amino acids upstream of the start of the transmembrane segment (RTKR, residues 640-643) , which would leave one potential N-glycosylation site in the C-terminal cleavage product. In order to confirm directly that proteolytic cleavage occurred at the RTKR (furin-recognized) site, site-directed mutagenesis was used to mutate this site to LTNR, and the effects of this mutation on the processing of the RPTPc precursor was examined. As shown in FIG. 12, the mutant cDNA gave rise to only a 210 kDa product. These results provide evidence that the RTKR region is the likely proteolytic cleavage signal and site for processing, of the RPTP/c proprotein. The inventors next tested whether the cleavage products were associated. This was accomplished by performing an immunoprecipitation with antiserum 116, specific for the extracellular 110 kDa product, on lysates of cells transfected with the wild type (wt) RPTP K cDNA. Immunoblotting of this precipitate with antiserum 122, specific for an intracellular RPTPc epitope, detected the presence of the 100 kDa C- terminal cleavage product in the precipitate (FIG. 12) . This observation strongly suggested that at least a portion of the two RPTP/c cleavage products remained associated after cleavage, and that the 100 and 110 kDa species may be considered as subunits of a single complex (FIG. 14). Experiments with a secreted form of the extracellular domain of RPTPc suggested that this association was not mediated by a disulfide linkage, since no association could be detected using SDS-PAGE under nonreducing conditions. A similar posttranslational processing event has been described for the RPTPase LAR and for the Ng-CAM protein (Burgoon, M. et al . 1992. J. Cell Biol. 112:1017-1029; Streuli, M. et al . , 1992 EMBO J. 11:897-907; Yu, Q. et al . , 1992 Oncogene 7:1051- 1057) . In addition, a potential cleavage site exists in the corresponding position in mRPTPμ (Gebbink et al . , supra) . It is therefore likely that proteolytic processing of RPTPs may be a more general phenomenon. Such cleavage, as described above, may allow controlled shedding of the N-terminal 110 kDa subunit, and thus render the membrane-bound 100 kDa form of RPTP/c insensitive to modulation by binding of proteins in the cellular environment. Alternatively, shedding might release a soluble species which retains binding activity to the putative RPTPc ligands. Interestingly, secreted soluble forms of extracellular domains have been described for tyrosine kinase receptors such as the FGF-receptor (Johnson, D.E. et 5 al . , Molec. Cell . Biol . 11:4627-4634 (1991)). However these secreted forms were generated by an alternative splicing mechanism. 10. EXAMPLE: ISOLATION AND ANALYSIS OF 0 HUMAN RPTPK (MCP7. cDNA CLONES 10.1. PCR AND CDNA CLONING METHODS Poly(A)+ RNA was isolated from SK-BR-3 cells 5 (ATCC HTB30) and cDNA synthesized using avian myeloblastosis virus (AMV) reverse transcriptase as described (Sambrook, J. et al . , MOLECULAR CLONING: A LABORATORY MANUAL, 2nd Edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (1989)). Polymerase o chain reaction using a pool of degenerated oligonucleotides based on two highly conserved regions of the PTPase domain (Vogel, W. et al . , Science 259:1611-1614 (1993) was performed under standard conditions, and PCR products were subcloned in 5 Bluescript KS+ vector (Stratagene) . Sequence analysis was done by the dideoxynucleotide chain termination method (Sanger et al. , 1977) using Sequenase (United States Biochemical) . a lambda ZAP 11 LIBRARY (Stratagene) from SK-BR-3 poly(A) + RNA was screened 0 with a PCR fragment probe under high stringency conditions (Ullrich, A. et al . . 1985, Nature 313:756- 711) . 5 10.2. RESULTS The complexity of PTPases expressed in the human breast cancer cell line SK-BR-3 was examined by performing a PCR analysis. The primers were degenerate sequences corresponding to conserved sequences within the PTP catalytic domains shared by all identified PTPases (Vogel, W. et al . 1993, Science 259:1611-1614) . Sequence analysis of the cloned PCR products revealed the presence of several known PTPases, including PTP1B, LAR, TC-PTP, PTP5, PTPe, PTPγ, and PTPH1, as well as some novel members of the PTPase family. One of the novel sequences, designated MCP7 ("mammary carcinoma-derived PTPase, clone 7"), was highly represented (18%) in the 121 clones examined. The 2066 bp MCP7 PCR fragment was used to screen a λ ZAP II SK-BR-3 cDNA library at high stringency. Eleven overlapping clones spanning an overall region of approximately 6.1 kb were analyzed, revealing an open reading frame encoding 1444 amino acids, followed by a 3• untranslated region of 1.8kb. The nucleotide sequence of human RPTPK (SEQ ID NO:4) is shown in FIG. 15(1) - (3). The deduced amino acid sequence of MCP7 (SEQ ID NO:2) is also shown in FIG. 15(1) - (3) and displays the structural organization of a type II transmembrane PTPase (Fischer et al., 1991, Charbonneau, H. et al. , Annu . Rev. Cell Biol . 8:463-493 (1992). The N-terminal hydrophobic stretch of 20-26 amino acids is typical of signal peptides (von Heijne, G., J . Mol . Biol . 184 : 99- 105 (1985) . A second region consisting of hydrophobic residues is found between positions 755 and 774 and is predicted to be a single helical transmembrane domain. It iε followed by a short region of mainly basic residues characteristic of a transfer stop εequence (Wickner, .T. et al . , Science 230:400-406 (1985)). The amino-terminal portion of the putative extracellular domain contains a sequence motif, a so called MAM domain, spanning a region of about 170 residues. The MAM structural motif was recently established by comparison of several functionally diverse receptors (including RPTPμ and the A5 protein) and is thought to play a role in cell adhesion (Beckmann et al. , supra) . This motif is followed by one possible Ig-like domain (residues 207-277) . The remaining extracellular portion contains conserved sequence motifs, indicating that it is composed of four FN-III related domains corresponding to the FN- III-like domains of LAR, PTP3 and RPTPμ. The extracellular domain contains 12 potential N- glycosylation sites, indicating that MCP7 is highly glycosylated. Interestingly, MCP7 contains the motif RXR/LR (residues 640-643) within the fourth FN-III domain. This motif has been described as the cleavage site for the subtilisin-like endoprotease, furin (Barr, P.J., Cell 66 : 1-3 (1991); Hosaka et al . , supra) . The cytoplasmic part of MCP7 is composed of two PTPase domains containing the conserved amino acid sequences typical of all known PTPases (Saito, H. et al . , Cell Growth Diff . 2:59-65 (1991)). A particularly intriguing feature is the region linking the transmembrane domain to the amino-terminal PTPase domain, which is nearly twice as large as that of most other receptor-like PTPases. A similar extended distance is shared only by the homologous PTPase, hRPTPμ (FIG. 16, lower line). The overall homology between MCP7 and hRPTPμ is 77%, to which the N- terminal and C-terminal PTPase domains contribute 91% and 86%, respectively (FIG. 16). 10.3. DISCUSSION The extracellular domain of MCP7 iε compoεed of one MAM domain, which iε a εequence motif spanning about 170 residues, which was recently eεtabliεhed by comparison of several functionally diverεe receptors (including RPTPμ and the A5 protein) and is thought to play a role in cell adhesion (Beckmann __ Bork, 1993, TIBS 18 . :40). The extracellular domain of MCP7 further includes one Ig-like, and four FN-type Ill-like segments. It therefore shares structural features with some cell adhesion molecules, permitting the classification of MCP7 into the type II PTPase claεs. MCP7 is highly homologous to mRPTPμ which has a more restricted expression pattern in lung, brain and heart (Gebbink et al. , supra) . MCP7 is expressed as a molecule consisting of two noncovalently linked subunits, a structural feature already shown for LAR. A similar processing motif was also determined within the extracellular domain of mRPTPμ (RTKR residues 632- 635) , which suggest that this structural organization is typical for the family of type II phosphatases. Proteolytic cleavage also occurs in the extracellular domain of the cell adhesion molecule Ng-CAM in a region containing the dibasic processing motif (Burgoon, M.P. et al., J. Cell . Biol . 112:1017-1029 (1991)). The functional significance of this structure is not yet clear. For LAR, a shedding of the extracellular E-subunit was observed in a density- dependent manner (Streuli et al . , supra) . It is likely that this shedding is due to a conformational change in the extracellular domain caused by homophilic or hydrophilic interactions between the molecules on the surface of neighboring cells that weakens the interaction between the noncovalently linked subunits. The effect of this shedding on the activity of the PTPase domains within the cells is not yet clear, but a modification of the activity of the phosphatase or a change in the sensitivity to modifying processes is probable. 11. EXAMPLE: TISSUE DISTRIBUTION OF HUMAN RPTPK 11.1. RNA EXTRACTION AND NORTHERN BLOT ANALYSIS Total RNA was isolated by the guanidinium isothiocyanate method (Chirgwin et al., 1979, Biochemistry 18_:5294-5299) from human tissue and cultured cells grown to confluency. Poly(A)+ RNA was prepared on an oligo(dT) column (Aviv & Leder, 1972, Proc. Natl. Acad. Sci. USA 69:1408-1412) . 4μg of poly(A)+ RNA was fractionated on a 1.2% formaldehyde- agarose gel and subεequently transferred to nitrocellulose filters (Schleicher & Schuell) . Hybridization was performed in 50% formamide, 5x SSC, 50mM NaH 2 P0 4 , pH 6.8, 0.5% SDS, 0.1 mg/ml sonicated salmon sperm DNA, and 5x Denhardt solution at 42°C overnight with 1-3 x 10 6 cpm/ml of 32 P- labeled random- primed DNA (United States Biochemical) . Filters were washed with 2x SSC, 0.1% SDS, and 0.2x SSC, 0.1%SDS at 45°C,and exposed 5 days using an intensifying screen at -80°C. 11.2. RESULTS Northern blot analysis revealed a broad tissue distribution of MCP7 (FIG. 17). The 6.7 kb transcript was found at elevated levels in lung and colon tisεue, and, to a lesser extent, in liver, pancreas, stomach, kidney, and placenta. No transcript was detected in spleen tissue. The expression pattern of MCP7 in different mammary carcinoma-derived cell lines is εhown in FIG. 18- Although MCP7 expreεsion was observed in all of the cell lines tested, the quantity of transcripts differed significantly. A second transcript with a size of 4.9 kb was also detected in all cell lines displaying a strong signal. Moreover, MDA-MB-435 cells contained a specific l.4kb mRNA that hybridized with the MCP7 probe. It is interesting to note that the intensity of the Northern hybridization signals shown in FIG. 18 correlate with the abnormal over expression of EGF-R and HER2/neu RTKs. Expression of MCP7 was alεo detected in human melanoma cell lines and some colon-carcinoma derived cell lines. 12. EXAMPLE: TRANSIENT EXPRESSION OF HUMAN RPTPK 12.1. METHODS MCP7 cDNA was cloned into a cytomegalovirus early promoter-based expression plasmid (pCMV) . The RTK expresεion plasmids used were described previously (Vogel, W. et al .. 1993 Science 259:1611-1614). At 30 hours prior transfection, 3x10 s cells of human embryonic kidney fibroblast cell line 293 (ATCC CRL 1573), grown in Dulbecco's modified Eagle's medium (DMEM) which included 4500 mg/1 glucose, 9% fetal calf serum, and 2mM glutamine, were seeded into a well of a six-well dish. Transfections with CεCl-purified plasmid DNA were then carried out using the calcium phosphate coprecipitation technique according to the protocol of Chen and Okayama (Chen, C. and Okayawa, H. , 1987; Mol. Cell. Biol. 7:2745-2752) with a total amount of 4μg, which included only 0.2μg expresεion plaεmid and complemented with empty vector DNA (Gorman, CM. et g .. 1989, Virology 121:377-385; Lammerε, R. et al . . 1990, J. Biol. Chem. 265:16886-16890.. At 16 hours after transfection, cells were washed once and starved with medium containing 0.5% fetal calf serum. For metabolic labeling, MEM containing Earle's salt, but lacking L-methionine, waε used instead of DMEM. [ 3i S] methionine at 40 μCi/ml (1,000 Ci/mmol) was added. Cells were stimulated with an appropriate ligand for 10 min. Epidermal growth factor (EGF) at 100 ng/ml waε used to stimulate cellε transfected with EGF-R, HER1/2, EK-R or EP-R. Insulin at 1 μg/ml waε used to εtimulate cells transfected with IR. SCF at 100 ng/ml was used to stimulate cells transfected with pl45 c " kit . After stimulation, cells were lyεed in 200 μl lyεis buffer (50mM HEPES, pH7.5; 150mM NaCl, 1.5mM MgCl 2 , ImM EGTA, 10% glycerol, 1% Triton X-100, 2mM phenylmethylsulfonylfluoride, lOμg/ml aprotinin, ImM Na-orthovanadate) . The lyεates were precleared by centrifugation at 125,000 x g for 10 min at 4°C, and 1/10 of the volume of the supernatant was mixed with SDS sample buffer. Proteins were separated by SDS-PAGE and transferred to nitrocellulose membranes. For detection of phosphotyrosine and protein antigens on immunoblotε, the ECL system (Amersham) in conjunction with horseradish peroxidase-conjugated goat anti-mouse or goat anti-rabbit antibody (Biorad) was used. In order to reprobe with other antibodies, blots were incubated for 1 hour in 67mM Tris-HCl (pH 6.8), 2% SDS, and 0.1% j8-mercaptoethanol at 50°C. For immunoprecipitation, radiolabelled cells were incubated with antiserum at 4°C for 2 hours, waεhed three ti eε with PBS (15mM NaCl, 3 mM Kcl, 80 mM Na 2 HPO 4 «H 2 0, 1.5mM KH 2 P0 4 , pH 7.4) to remove unbound antibodieε, lysed, and precleared by centrifugation. Protein A-εepharoεe (Pharmacia) in a volume of 20 μl has added and incubated for two hours on a rotating wheel at 4 β C. Precipitates were washed four times with HNTG-buffer (20mM HEPES, ph. 7.5, 150 mM Na Cl, 0.1% Triton X-100,. 10* glycerin), SDS-εample buffer added, and SDS-PAGE was performed. X-ray film was then exposed to the dried gel two dayε. The polyclonal antiεerum, Ab 116, εpecific for the extracellular domain of murine RPTP/c, waε raiεed against a peptide sequence (residues 60-76) within the extracellular domain of the mouse homolog of MCP7, and which was perfectly conserved in the human sequence as deεcribed supra , in Section 10. The monoclonal antibody εpecific for phosphotyrosine, 5E.2, was described previously (Fendly, B.M. et al . . 1990, Cane. Res. .50:1550-1558). 12.2. RESULTS Forty eight hours after transfection of MCP7 cDNA, using a cytomegalovirus promoter-based expression vector, into 293 embryonic kidney cellε, radiolabelled cells were incubated with Ab 116. Cells were washed, lysed, and the antibody-bound material was immunoprecipitated. MCP7 expreεsion was found on the cell surface only, and appeared as a band having an apparent molecular weight of 185 kDa. The larger size than the calculated molecular weight of 163 kDa was probably due to extensive glycosylation of the extracellular domain. Two additional bands of 97 kDa and 116 kDa were immunoprecipitated (FIG. 19, left panel, lane 1); these bands were not detectable in cells transfected with a control vector. Such lower molecular weight products were thought to be cleavage productε since the extracellular domain contains a common cleavage motif (RXR/LR; residues 640-643, FIG. 15(l)-(3)). for processing by the endoprotease furin. These products are similar to the cleavage products described above for murine RPTP/c. Furthermore, similar processing of the extracellular domain of LAR has been described (Streuli et al . , supra) . The 6 kDa fragment, the α subunit, represents moεt of the extracellular domain and is highly glycosylated, aε indicated by the broadneεε of the band upon polyacrylamide gel electrophoresis analysiε and itε apparent molecular weight, which exceeded the calculated value, baεed on the εequence between reεiding 20 and 639, by 47kD. The 97 kDa fragment, the β εubunit, correεponds to an intracellular and transmembrane domain and also includes a short extracellular segment which is thought to interact with the α subunit. The relatively minor discrepancy between the observed 97 kDa molecular weight size and the calculated 91.4 kDa molecular weight of the β subunit can be explained by the presence of only one potential N-glycosylation site. The α and β subunit are believed to form a stable complex, εuch that immunoprecipitation by an antibody εpecific for the extracellular domain would detect both εubunitε. To confirm that the 116 kDa band corresponded to the α subunit cleavage product and not merely to a non-specifically croεε-reacting species, lysateε from MCP7 cDNA-tranεfected 293 cells were subjected to Western blots uεing antiεerum 116 εpecific for an N-terminal epitope. With thiε approach, a band of about 116 kDa aε well as an unproceεsed precursor were found (FIG. 19, right panel, lane 1) , neither of which were detected in 293 cells at comparable levels transfected with a control vector (FIG. 19, right panel, lane 2). 13. EXAMPLE: EXAMINATION OF PTPase ENZYMATIC ACTIVITY OF HUMAN RPTP/c To prove that the RPTP/c designated MCP7 is indeed a PTPase enzyme, the above transient expression syεtem in 293 cellε waε used. Coexpression of MCP7 with a panel of different RTKs representing different structural subclasses allowed the examination of more physiological substrates for the PTPase as dephosphorylation targets than those commonly used. To ensure that the protein localized mainly in the membrane and to avoid an overload of the cell transport system, these transfection experiments were performed with only small amounts of plasmid compared to the original protocols (Gorman, CM. et al . , Virology 171:377-385 (1989); Lammers, R. et al . , J. Biol . Chem . 265:16886-16890 (1990)). The receptors tested were mainly chimeric receptors, the respective kinase function of which was under the control of an EGF-R extracellular domain (Lee, J. et al . , EMBO J . 8:167-173 (1989); Herbst, R. et al. , J . Biol . Chem . 266:19908-19916 (1991); Seedorf, K. et al . , J . Biol . Chem . 266:12424-12431 (1991)). Human 293 fibroblasts were tranεfected with equal amounts of expression plasmidε encoding for an RTK and either MCP7 or a control vector. After stimulation with the appropriate ligand for the RTK, cells were lysed, equal aliquots were resolved by SDS PAGE, and the phosphotyrosine level of the receptors was examined by immunoblotting with the anti-phosphotyrosine antibody 5E2 (Fendly, G.M. et al . , Cane. Res . 50:1550-1558 (1990)) . Co-expression of I-R, EGF-R, EP-R, EK-R, and SCF- R/c-kit with MCP7 resulted in a marked decrease in theligand-induced receptor phosphotyroεine content when compared with control transfections in which MCP7 expression plasmid had been omitted (FIG. 20, upper panel, lanes 1 and 9; lower panel, lanes 1, 5, and 9). In contrast, HER1-2 appeared to be a poor substrate of MCP7, since only weak reduction of the ligand-induced phosphorylation state of this chimera waε obεerved (FIG. 20, upper panel, lane 5) . Intereεtingly, the intracellularly localized, incompletely proceεεed precursor forms of I-R, EGF-R and EP-R (FIG. 20, upper panel, lanes 2, 4 and 10, 12; lower panel, laneε 2, 4), aε well as that of HER 1-2 (FIG. 20, upper panel, lanes 6, 8) , were efficiently dephosphorylated) , suggeεting that MCP7 waε preεent and active in the same intracellular compartments as the co-expresεed RTKs before reaching the cell surface. To verify the above effects and to rule out differences in RTK expression levelε, the above blots were re-probed with RTK-specific and RPTP/-specific antibodieε. The results indicated that expression levels of the various RTKs were equivalent. 14. EXAMPLE: CORRELATION BETWEEN HUMAN RPTPK EXPRESSION AND CELL DENSITY The presence of motifs in the extracellular domain of human RPTP/c that resemble motifs found in proteinε involved in cell-cell and cell-extracellular matrix interactions prompted an investigation of the effect on expression level of cell density in culture. An equal number of SK-BR-3 cells waε diεtributed onto either one, two, or four 15-cm dishes and incubated for two days under standard growth conditions. When harvested after two days, cells seeded at the various starting densities were found to be 100%, 70%, and 40% confluent, respectively. Poly(A)+ RNA was prepared and Northern blot analysis was conducted as described supra , in Section 11.1, using a probe corresponding to the extracellular domain of MCP7. The resultε indicated that the level of MCP7 tranεcriptε increaεed with increaεed cell denεity (FIG. 21, left panel) . To determine whether thiε effect was unique to SK-BR-3 cellε, an identical experiment waε performed uεing the colon carcinoma-derived cell line HT 29. Expreεεion of MCP7 mRNA was also found to be density- dependent with these cells (FIG. 19, right panel). Aε a control, the expreεsion of mRNA encoding the enzyme GAPDH waε examined in the above cellε at variouε densities. No density dependence of the expresεion of theεe tranεcriptε were obvεerved. The above reεults εupport the hypotheεis RPTP/c, and other RPTPs of the type II and type III families, are involved in, and modulated by, cell adhesion events (Charbonneau et al. , supra) . PTPases appear to be involved in events leading to growth arrest by cell-cell contact (Klarlund, supra) . The presence of orthovanadate, a potent inhibitor of phosphatase activity dimisheε normal contact inhibition of 3T3 cellε. Furthermore, PTPaεe activity aεεoCiated with the membrane fraction of 3T3 cellε increased 8 fold when cells were grown to a higher density (Pallen, CJ. et al . , Proc. Natl . Acad . Sci . USA 88:6996-7000 (1991)). The combination of CAM motifε in the extracellular domain or RPTP/c and the intracellular PTPase activity indicates that RPTP/c may act as an important mediator of events associated with arrest of cell growth. The structural features of human RPTPc described above, the denεity-dependent upregulation or itε expreεsion, and its potent activity in dephosphorylating RTKs supports the emerging picture of the pivotal role of RPTP/c in growth arrest through contact inhibition, aε well as a role as a tumor suppressor gene. 15. Example: Homophilic Binding by a Receptor Tyrosine Phoεphataεe The present work inveεtigateε whether, εimilar to ■■ classical" members of the CAM family, RPTPases might be capable of homophilic intercellular interaction (Q . Yu, T. Lenardo, R.A. Weinberg, Oncogene 7, 1051 (1992)). Reasoning that analysis of cell adhesion by the RPTPaεe RPTP/c would be facilitated by itε ectopic expreεεion in a cell line likely to lack conεerved ligandε for a mammalian RPTPaεe, we εtably introduced an RPTPc cDNA into Drosophila S2 cellε. These cells have a very low capacity for spontaneous aggregation or adhesion, making them an ideal and establiεhed εyεte for εuch εtudies (H. Kramer, R.L. Cagan, S.L. Zipurεky, Nature 352, 207). Cellε transfected with a vector containing the RPTPK cDNA in the sense orientation with respect to the heat-shock protein 70 (hsp 70) promoter of the vector, and induced by brief heat treatment expressed a protein of 210 kD detectable by immunoblotting with anti-RPTPc antiserum (FIG. 22A) . This protein correεpondε to the unprocessed form of RPTP/c seen in mammalian cells (Y.- P. Jiang et al. Mol. Cell. Biol. 13, 2942 (1993)). In addition, after longer expression periods, a protein species of 110 kD also appeared, εuggesting that the RPTPc protein may at least, in part, partly be processed in the Drosophila cell line in a manner similar to the way in which it is processed in mammalian cells, i.e.. through proteolytic cleavage by a furin type endoprotease (FIG. 22A) (Y.-P. Jiang et al . Mol. Cell. Biol. 13, 2942 (1993)). A Drosophila furin homolog has recently been deεcribed (A.J.M. Roebroek et al., EMBO J. 12, 1853 (1993)). In order to study whether RPTPc expression may mediate cell-cell aggregation, cells stably transfected with the RPTP/c CDNA in either the sense orientation (sense cDNA) or the antisenεe orientation (antisense cDNA) were tested in an aggregation asεay. uninduced and heat εhock-induced cellε were reεuεpended, εubjected to rotary εhaking to enεure mixing and to avoid adheεion to the veεεel, and were then assayed for aggregate formation. The formation of a large number of aggregates consiεting of more than 10 and up to approximately 100 cellε was observed in heat-εhocked senεe cDNA-expreεεing cellε only, whereaε control cellε (i.e. , antisense cDNA transfected cells or non-heat shocked cellε) remained eεsentially single cell suspensionε (FIG. 22B) . Two methodε of quantitation, counting of aggregateε under the microεcope, and determination of εuper-threεhold particles with a Coulter-counter (FIG. 22C) confirmed this conclusion. The fact that aggregation was incomplete, with a large proportion of RPTP/c tranεfected cellε remaining aε single cellε throughout the aεsay period, is most likely due to the fact that the transfected cell population consisted of an uncloned pool of cellε presumably differing in their levels of RPTPK expression. Notably, the conditions of the assay (i.e.. medium, timescale, and speed of shaking) are similar to those used to demonstrate the adhesive properties of a number of well established adhesion molecules (H. Kramer, R.L. Cagan, S.L. zipursky. Nature 352, 207 (1991); P.M. Snow, A.J. Bieber, C. Goodman, Cell 59, 313 (1989)). Therefore, in view of the difficulty of measuring binding affinities of many cell adhesion molecules which rely on cooperativity, it iε likely that the εtrength of cell-cell-interaction conferred by expreεsion of RPTPK is comparable to that of establiεhed, "classical", cell adhesion molecules. The above experiments were performed with a full- length RPTPK cDNA, leaving unclear whether the phosphataεe activity of the intracellular domain iε required to confer adheεive propertieε. In εeveral inεtanceε, an intact intracellular domain of cell adhesion molecules has in fact been shown to be required for certain aspectε of cell-cell interaction (A. Nafaguchi and M. Takeichi, EMBO J. 7, 3679 (1988); S.H. Jaffe et al . , Proc. Natl. Acad. Sci. USA 87, 3589 (1990), R.O. Hynes, Cell 69,111 (1992)). To teεt this isεue, a cDNA encoding a mutant protein lacking moεt of the intracellular, catalytic, domain of RPTPK was constructed. Fig. 22D shows that such a truncation did not negatively interfere with cell aggregation aε measured in this type of assay. The role of the furin cleavage site in the extracellular domain of RPTPK was also teεted. Mutation of this εite alεo left the adheεive behavior intact, εuggeεting that cleavage of the RPTPK proprotein (Y.-P. Jiang et al . Mol. Cell. Biol. 13, 2942 (1993)) iε not required for induction of cell aggregation. Cell adhesion molecules have been described which either do (e.g. cadherin family members and integrins) , or do not (e.g. N-CAM, Ng-CAM) require the presence of Ca ++ (G.M. Edelman, Immun. Rev. 100, 11 (1987); A.F. Williams and A.N. Barclay, Annu. Rev. Immunol. 6, 381 (1988); M. Grumet, Curr. Opin. Neurobiol. 1, 370 (1991), R.O. Hynes, Cell 69,111 (1992), B. Geiger and 0. Ayalon, Annu. Rev. Cell Biol. 8 (1992)). The experiments presented in FIG. 22 were performed in the presence of 10 mM Ca ++ in the aggregating cell suεpenεion. Performing a similar experiment in the absence of calcium ions and in the presence of 1 mm EGTA revealed no calcium requirement for RPTPK mediated cellular aggregation under the conditions of the assay. The observed aggregation correlating with expresεion of RPTPK could be accounted for by either a homophilic binding mechaniεm, in which cell-cell binding iε mediated by interaction between RPTPK proteinε on different cellε within aggregates, or by binding of the RPTPK protein to a second cell-surface ligand intrinsic to the parental transfected cells. It was possible to distinguish between these two hypotheses by marking different populations of cells with the fluorescent lipophilic dye 1,1'-dioctadecyl- 3,3,3• ,3'tetramethylindocarbocyanine perchlorate (dil) (j. Schlessinger et al . Science 195, 307 (1977)), and then teεting them for their ability to co-aggregate. In these experiments, RPTPK expressing and non- expressing cells were labeled with dil, mixed with unlabeled cells of either RPTPK expressing or non- expresεing types, and the presence of cells of either type in the aggregates formed was monitored by fluoreεcence microεcopy. The reεults are illustrated in FIG. 23. Strikingly, mixing of unlabeled, RPTPK positive cells with labeled, RPTPK negative cells led to the formation of aggregates consisting exclusively of unlabeled cells. Conversely, when the RPTPK expressing cells were labeled and allowed to aggregate with unlabeled control cells, aggregates consisted entirely of labeled cells, demonstrating that dil labeling does not interfere with the aggregation capacity of the transfected cells. Mixing of labeled and unlabeled cellε, both expreεεing RPTPK, led to the formation of mixed aggregates consisting of cells of either staining type, thus confirming that both dil stained and unstained cellε have the ability to co- aggregate. Theεe reεultε εuggeεt that aggregation of the RPTPK tranεfected cellε requireε the preεence of the protein on all cells within the aggregate, implying a homophilic binding mechanism. It was next determined whether the extracellular domain of RPTPK was able to function by itself aε a εubεtrate for attachment of cellε expreεεing the RPTPK protein independent of other factorε to aεsist in the adhesion proceεs. A baculovirus expression syεtem waε uεed to produce a εoluble recombinant protein conεisting of virtually the entire extracellular domain of the RPTPK protein, fused to placental alkaline phosphataεe, which εerved aε a tag for purification and detection (J.G. Flanahan and P. Leder, Cell 63, 185 (1990)). Fuεion between the two protein moieties was designed to occur precisely before the furin proteolytic cleavage signal in the fourth fibronectin type III repeat in RPTPK (Y.-P. Jiang et al. Mol. Cell. Biol. 13, 2942 (1993)). The purified recombinant protein (K2AP) was used to coat bacteriological Petri dishes, and monitored for itε ability to allow attachment of RPTP -expresεing S2 cellε. Only induced, RPTPK expreεεing cellε εhowed adheεive behavior to the K2AP coated εurface (FIG. 24; Table II below) . TABLE I I Cell S2 control S2 control S2-R-FTP-I. S2-R-PTP-X L6 L6R- type: PTP-«: un-induced induced un-induced induced Protein K2ΛP-» - - - + + + + + + K2AP-b - - - + + + + + + AP - . - - - HER - - - - - - BSA - - - - - - Fibro¬ + + + + + + + + + + + + + + nectin poly- n.d. n.d. n.d. n.d. + + + + + -. lyiine Summary of adhesion data of different cell typeε to surfaces coated with purified K2AP protein, or other proteins (-:no cells attached; + : 50-150 cells; ++ 150-500; +++:>500; n.d. : not determined) K2APa: K2AP protein purified by elution from affinity column at alkaline pH. K2APb: K2AP protein purified by elution from affinity column using 50 % ethylene glycol. AP: alkaline phosphataεe control protein (J.G. Flanahan and P. Leder, Cell 63, 185 (1990)), correεponding to the tag portion of the K2AP fuεion protein. HER: Human EGF-receptor extracellular domain affinity- purified from a baculovirus expresεion εyεtem (I. Lax et al., J. Biol. Chem. 266, 13828 (1991)). BSA: bovine serum albumin. L6-R-PTPκ : a clone of L6 cells stably transfected with the R-PTPK protein. No attachment occurred to control coated surfaceε, which included alkaline phoεphataεe or the recombinant extracellular domain of human EGF-receptor (I. Lax et al., J. Biol. Chem. 266, 13828 (1991)), also purified by affinity chromatography from a baculovirus expresεion εyεtem. Whereas the above experiments were performed in the context of insect cellε, the effect of RPTPK protein expression in mammalian cells in a similar cell-to-substrate adhesion assay was also tested. In contrast to parental Drosophila S2 cellε, rat L6 myoblaεt cellε, the mammalian cell line uεed aε a recipient for RPTPK overexpreεsion, already showε a low level of εpontaneous adhesion to a K2AP protein coated surface. However, stable overexpresεion of an RPTPK CDNA in theεe cells led to a significant (2.7 fold +/-1.0; n=3) increase in adhesive capacity to a surface coated with the recombinant soluble extracellular domain of the RPTPK protein (FIG. 24). 15.1 Discuεεion Cell-cell contact iε generally considered to play a critical role in various aεpectε of malignancy. For example, eεcape from contact inhibition is a classical parameter of transformation, and, additionally, many links between cell-cell interactions and εuch phenomena aε tumor invasion and metastaεiε are apparent (F. Van Roy and M. Mareel, TICB 2, 163 (1992)). The above data clearly demonεtrate that an RPTPaεe of the LAR-like εubfamily (containing a combination of Ig and fibronectin type III domains) iε capable of homophilic binding between neighboring cellε, leading to the identification of a function for the extracellular domains of εuch molecules. This makeε it likely that other memberε of thiε RPTPase εubfamily can behave in a εimilar faεhion, and extendε the series of links that have recently emerged between the adhesive propertieε of cellε, and εignal tranεduction pathwayε involving tyroεine phosphorylation. For instance, adherens junctionε correspond to sites of increased tyrosine phosphorylation and appear to be subject to its control, and reagents directed at integrinε or extracellular domains of established CAMs have been shown to elicit changes in cellular tyrosine phosphorylation (J.R. Atashi et al. , Neuron 8, 831 (1992); T. Volberg et al . , EMBO J. 11, 1733 (1992); R.L. Juliano and S. Haskill, J. Cell Biol. 120, 577 (1993)). In addition, reagents directed toward cell adhesion molecules are known to activate a number of second meεsenger signalε (Schuch, U. Lohεe, M. Schachner, Neuron 3, 13-20 (1989); P. Doherty, S.V. Aεhton, S.E. Moore, F. Walsh, Cell 67, 21 (1991)). The above obεervation suggests mechanismε by which εuch signals might be generated. For example, direct cell-cell contact between RPTPaseε on adjacent cellε could lead to local RPTPaεe oligomerization events affecting either the catalytic activity or localization of RPTPaseε, which in turn have been suggested to modulate the activity of src-family tyrosine kinaseε (H. L. Oεtergaard et al . , Proc. Natl. Acad. Sci. USA 86, 8959 (1989); T. Muεtelin and A. Altman, Oncogene 5, 809 (1989) ; X.M. Zheng, Y. Wang, CJ. Pallen, Nature 359, 336 (1992)). Moreover, the similar structural and functional properties of the extracellular domains of RPTPases and CAMs prompts the speculation that RPTPases may, in addition to self- interaction, alεo be capable of interacting heterophilically with other molecules involved in cell adheεion, whether in cis or in trans (G.M. Edelman, Immun. Rev. 100, 11 (1987); A.F. Williams and A.N. Barclay, Annu. Rev. Immunol. 6, 381 (1988); M. Grumet, Curr. Opin. Neurobiol. 1, 370 (1991) , R.O. Hyneε, Cell 69,111 (1992), B. Geiger and 0. Ayalon, Annu. Rev. Cell Biol. 8 (1992) , M. Grumet and G.M. Edelman, J. Cell Biol. 106, 487-503 (1988); G.A. Kadmon, A. Kowitz, P. Altevogt, M. Schachner, J. Cell Biol. 110, 193 (1990); A.A. Reyes, R. Akeεon, L. Brezina, G.J. Cole, Cell Reg. 1, 567 (1990); P. Sonderegger and F. G. Rathjen, J. Cell Biol. 119, 1387 (1992); M.G. Grumet, A. Flaccuε, R.U. Margolis, J. Cell Biol. 120, 815 (1993)). The references cited above are all incorporated by reference herein, whether specifically incorporated or not. Having now fully described thiε invention, it will be appreciated by thoεe εkilled in the art that the εame can be performed within a wide range of equivalent parameters, concentrations, and conditionε without departing from the εpirit and εcope of the invention and without undue experimentation. While thiε invention haε been deεcribed in connection with εpecific embodimentε thereof, it will be underεtood that it iε capable of further modifications. This application iε intended to cover any variationε, uεes, or adaptations of the inventions following, in general, the principleε of the invention and including εuch departureε from the preεent disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore εet forth aε followε in the εcope of the appended claims.

Claims: WHAT IS CLAIMED IS: 1. An isolated mammalian receptor-type protein tyrosine phosphataεe K protein or glycoprotein molecule. 2. The molecule of Claim 1 wherein the molecule compriseε the amino acid sequence SEQ ID NO:l, εhown in FIG. 3. 3. The molecule of Claim 1 wherein the molecule is a human receptor-type protein tyrosine phosphatase . The molecule of Claim 3 wherein the molecule comprises the amino acid sequence SEQ ID NO:2, shown in FIG. 15. 5. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the receptor-type protein tyroεine phoεphataεe K protein of Claim 1. 6. The nucleic acid of Claim 5 wherein the nucleotide sequence encoding the receptor-type protein tyroεine phoεphataεe K protein iε the nucleotide εequence SEQ ID No:3, εhown in FIG. 1(1) - 1(5). 7. An iεolated nucleic acid molecule compriεing a nucleotide εequence encoding the human receptor-type protein tyroεine phoεphataεe K protein of Claim 3. 8. The nucleic acid molecule of Claim 7 wherein the nucleotide εequence encoding the human receptor- type protein tyroεine phosphatase /. is the nucleotide sequence SEQ ID NO: , shown in FIG. 15(1) - 15(5). 9. The nucleic acid molecule of Claim 5 or 7 wherein the nucleic acid molecule is cDNA. 10. The nucleic acid molecule of Claim 5 or 7 wherein the nucleic acid is genomic DNA. 11. The nucleic acid molecule of Claim 5 or 7 wherein the nucleic acid molecule iε an expression vehicle. 12. The nucleic acid molecule of Claim 11 wherein the expresεion vehicle iε a plaεmid. 13. A prokaryotic host cell having the plasmid of Claim 12. 14. A eukaryotic host cell having the plasmid of Claim 12. 15. A method for preparing the receptor-type protein tyrosine phosphataεe K protein or glycoprotein of Claim 1, compriεing: (a) culturing a hoεt cell capable of expressing the protein or glycoprotein under culturing conditions that permit expression of the protein or glycoprotein; and (b) recovering the protein or glycoprotein from the culture. 16. The method of Claim 15 wherein the host cell is a prokaryotic cell. 17. The method of Claim 15 wherein the host cell is a eukaryotic cell. 18. An antibody specific for the protein or glycoprotein of Claim 1. 19. The antibody of Claim 18 wherein the antibody is a monoclonal antibody. 20. A method for detecting the presence of the nucleic acid molecule of Claim 5 in a cell, comprising: (a) contacting the cell with a nucleic acid probe capable of specifically hybridizing to least a portion of the nucleic acid molecule of Claim 5 under hybridizing conditions; and (b) measuring the hybridization of the probe to the nucleic acid of the cell, thereby detecting the presence of the nucleic acid sequence. 21. A method for detecting the presence of the nucleic acid molecule of Claim 5 in a cell, comprising: (a) contacting the cell with nucleic acid primers capable of specifically binding to at least a portion of the nucleic acid molecule of Claim 5 under hybridizing conditionε; (b) selectively amplifying at least a portion of the nucleic acid molecule of Claim 5; and (c) detecting the amplified nucleic acid of the cell, thereby detecting the presence of the nucleic acid sequence. 22. A method for detecting in a cell the presence of or measuring the quantity of a receptor protein tyrosine phosphataεe K protein or glycoprotein, comprising: (a) contacting the cell or an extract thereof with the antibody of Claim 18; and (b) detecting binding of the antibody to the cell or extract thereof, or measuring the quantity of antibody bound, thereby determining the presence of or measuring the quantity of the receptor protein tyroεine phosphatase/c protein or glycoprotein. 23. A method for identifying in a chemical or biological preparation a compound capable of binding to the receptor protein tyrosine phosphatase K protein, glycoprotein or derivative of Claim 1, comprising: (a) attaching the receptor protein tyrosine phoεphataεe K protein, glycoprotein or derivative, or the ligand-binding portion thereof, to a solid phase matrix; (b) contacting the chemical or biological preparation with the solid phase matrix allowing the compound to bind; (c) washing away any unbound material; and (d) detecting the presence of the compound bound to the solid phaεe matrix. 24. A method for isolating from a complex mixture a compound capable of binding to the receptor protein tyroεine phoεphatase K protein or glycoprotein of Claim 1, comprising: (a) attaching the receptor protein tyroεine phoεphataεe K , or the ligand-binding portion thereof, to a εolid phaεe matrix; (b) contacting the complex mixture with the εolid phaεe matrix allowing the compound to bind; (c) waεhing away any unbound material; and (d) eluting the bound compound, thereby isolating the compound. 25. A method for identifying an agent capable of modulating the enzymatic activity of receptor protein tyrosine phosphatase /., comprising: (a) contacting the agent with a receptor protein tyroεine phoεphataεe K in pure form, in a membrane preparation, or in a whole cell; (b) incubating the mixture of εtep (a) for a sufficient interval; (c) measuring the enzymatic activity of the receptor protein tyrosine phoεphatase*; and (d) comparing the enzymatic activity to that of receptor protein tyroεine phosphatase/c incubated without the agent, thereby determining whether the agent modulates enzymatic activity. 26. The method of Claim 25 wherein the agent iε capable of decreaεing the activity of the receptor protein. 27. The method of Claim 25 wherein the agent iε capable of inhibiting the activity of the receptor protein. 28. A method for inhibiting homophilic binding of endogenouε Type II receptor protein tyroεine phoεphataεe molecules in a mammal comprising administering to the mammal an effective amount of an inhibitory compound so that the homophilic binding is inhibited. 29. The method of Claim 28 wherein the homophilic binding is intercellular. 30. The method of Claim 28 wherein the inhibitory compound compriεeε an extracellular domain of a Type II receptor protein tyroεine phoεphataεe molecule. 31. The method of Claim 28 wherein inhibiting of homophilic binding modulateε the endogenouε enzymatic activity of the Type II receptor protein tyrosine phosphataεe molecules. 32. The method of Claim 31 wherein the endogenouε enzymatic activity of the Type II receptor protein tyroεine phosphatase molecules is increased. 33. The method of Claim 31 wherein the endogenouε enzymatic activity of the Type II receptor protein tyroεine phoεphataεe moleculeε iε decreaεed. 34. The method of Claim 28 or 31 wherein inhibiting homophilic binding of endogenouε Type II receptor protein tyrosine phosphataεe molecules regulates a cellular function comprising differentiation or cell cycle control. 35. The method of Claim 28 or 31 wherein inhibiting homophilic binding of endogenous Type II receptor protein tyrosine phosphataεe moleculeε regulates cellular behavior comprising motility, contact inhibition, cell adhesion, or signal transduction. 36. The method of Claim 28 or 31 wherein inhibiting homophilic binding of endogenous Type II receptor protein tyrosine phosphatase molecules regulates an abnormal or deleterious process comprising cellular transformation to a cancerous state. 37. A method for inhibiting homophilic binding of endogenous receptor-type protein tyrosine phosphatase K molecules comprising adminiεtering to the mammal an effective amount of an inhibitory compound so that the homophilic binding is inhibited. 38. The method of Claim 37 wherein the homophilic binding is intercellular. 39. The method of Claim 37 wherein the inhibitory compound comprises a soluble receptor-type protein tyrosine phoεphataεe *c protein extracellular domain. 40. The method of Claim 37 wherein inhibiting homophilic binding of endogenouε receptor-type protein tyrosine phosphataεe K protein modulates endogenous receptor-type protein tyrosine phosphatase K enzymatic activity. 41. The method of Claim 40 wherein the endogenouε enzymatic activity of the receptor-type protein tyroεine phosphatase K protein is decreaεed. 42. The method of Claim 40 wherein the endogenouε enzymatic activity of the receptor-type protein tyroεine phoεphataεe K protein iε increaεed. 43. The method of Claim 37 or 40 wherein inhibiting homophilic binding of endogenouε receptor- type protein tyrosine phosphatase K molecules regulates a cellular function comprising differentiation or cell cycle control. 44. The method of Claim 37 or 40 wherein inhibiting homophilic binding of endogenous receptor- type protein tyrosine phosphatase K molecules regulates a cellular behavior comprising motility, contact inhibition, cell adhesion, or signal transduction. 45. The method of Claim 37 or 40 wherein inhibiting homophilic binding of endogenouε receptor- type protein tyroεine phoεphataεe K moleculeε regulates an abnormal or deleterious process comprising cellular transformation to a cancerous state. 46. A method for identifying a compound capable of inhibiting homophilic binding of Type II receptor- type protein tyroεine phoεphatase molecules comprising: (a) exposing an immobilized molecule comprising a Type II receptor-type protein tyrosine phoεphataεe protein extracellular domain to a Type II receptor- type protein tyrosine phosphataεe protein molecule and a compound; (b) removing all molecules that do not attach to the immobilized molecule; and (c) determining if the Type II receptor-type protein tyrosine phosphataεe protein molecule bindε the immobilized molecule. 47. A method for identifying a compound capable of inhibiting homophilic binding of Type II receptor- type protein tyrosine phosphatase molecules comprising exposing Type II receptor-type protein tyrosine phosphataεe-expressing cells to a compound and determining if the Type II receptor-type protein tyrosine phosphataεe-expressing cells aggregate. 48. The method of Claim 46 or 47 wherein the Type II receptor-type protein tyrosine phosphatase molecule is receptor-type protein tyroεine phoεphataεe K.

Inventors: FUCHS MIRIAM, SAP JAN M, SCHLESSINGER JOSEPH, ULLRICH AXEL, VOGEL WOLFGANG, FUCHS, MIRIAM, SAP, JAN, M., SCHLESSINGER, JOSEPH, ULLRICH, AXEL, VOGEL, WOLFGANG
Applicants: MAX PLANCK GESELLSCHAFT, UNIV NEW YORK, MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSC, NEW YORK UNIVERSITY MEDICAL CENTER
Application year: 1994
Main classification: C07K13
IPC codes: A61K39, A61K45, C07H21, C07K14, C07K16, C12N5, C12N9, C12N15, C12P21, C12Q1, C12R1, G01N33